Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors

ABSTRACT

The present invention provides methods for the treatment of obesity using sterol or 5α-stanol absorption inhibitors and compositions and therapeutic combinations including sterol or 5α-stanol absorption inhibitors and at least one obesity control medication.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. ProvisionalPatent Application Ser. No. 60/323,840, filed Sep. 21, 2001, and is acontinuation-in-part of U.S. patent application Ser. No. 10/166,942,filed Jun. 11, 2002, each incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compositions and therapeuticcombinations for treating obesity in a subject comprising theadministration of sterol and/or 5α-stanol absorption inhibitor(s) orcombinations with obesity control medications.

BACKGROUND OF THE INVENTION

Obesity is one of the most common medical problems in the United Statesand other developed countries and a risk factor for other illnesses,such as hypertension, diabetes, degenerative arthritis and myocardialinfarction. Weight loss medications may be appropriate for use inselected patients who are obese or who are overweight with co-morbidconditions.

One measure for defining obesity is known as a body mass index (BMI),which is weight in kilograms divided by height in meters squared. A BMIof 18.5 to 24.9 is generally classified as normal, a BMI of 25.0 to 29.9is generally classified as overweight and a BMI of 30 or greater isgenerally classified as obese. Alternatively, obesity may be defined asthe top percentile, such as 15 percent, of a population's weight for agiven height. Such definitions of obesity, however, are not a measure ofbody composition and different people may have higher or lower levels ofbody fat or muscle mass for their height. Nevertheless, thesedefinitions of obesity are useful characterizations for generalpopulations of people.

The goal of obesity treatment is to exert a negative energy balance onthe system by reducing energy input or increasing energy output, orboth. Obesity is caused by a constellation of factors including, but notlimited to, excessive energy intake (food), insufficient energy output(exercise), low resting metabolic rate, genetic predisposition, low fatoxidation rate, low sympathetic activity and high plasma leptin level.These factors may also have several causes. For example, a low restingmetabolic rate may be due to genetic variation involving sympatheticactivity, thyroid activity, β3-receptor sensitivity, and adenosinetriphosphatase enzyme activity. Genetic factors may include a mutationin the gene coding for the β3-adrenergic receptor causing lowβ3-adrenergic activity which promotes obesity by slowing lipolysis andcausing retention of lipids in fat cells. Moreover, as weight is lost byrestricted energy intake, fat cells shrink, reducing expression ofleptin, a product of the ob gene. As leptin levels fall, metabolic ratedecreases, and appetite increases, thereby generally impeding furtherweight loss. Thus, obesity control medications are often formulated toreduce energy intake or suppress appetite, increase energy output ordecrease the absorption of nutrients by various different approaches.

Despite the current approaches for the treatment or prevention ofobesity, there remains a need in the art for improved compositions andtreatments for obesity.

SUMMARY OF THE INVENTION

One embodiment of the present invention provides a compositioncomprising (a) at least one obesity control medication; and (b) at leastone sterol absorption inhibitor and/or at least one 5α-stanol absorptioninhibitor or a pharmaceutically acceptable salt thereof or a solvatethereof.

Therapeutic combinations also are provided comprising: (a) a firstamount of at least one obesity control medication; and (b) a secondamount of at least one sterol absorption inhibitor and/or at least one5α-stanol absorption inhibitor or a pharmaceutically acceptable saltthereof or a solvate thereof, wherein the first amount and the secondamount together comprise a therapeutically effective amount for thetreatment or prevention of obesity or lowering a concentration of asterol or 5α-stanol in plasma of a subject.

Pharmaceutical compositions for the treatment or prevention of obesityor lowering a concentration of a sterol or 5α-stanol in plasma of asubject comprising administering a therapeutically effective amount ofthe above compositions or therapeutic combinations and apharmaceutically acceptable carrier also are provided.

Methods of treating or preventing obesity or lowering a concentration ofa sterol or 5α-stanol in plasma of a subject, comprising the step ofadministering to a subject in need of such treatment an effective amountof the above compositions or therapeutic combinations also are provided.

Methods of treating or preventing obesity comprising the step ofadministering to a subject in need of such treatment an effective amountof a composition comprising at least one sterol absorption inhibitorand/or 5α-stanol absorption inhibitor also are provided.

A method of treating or preventing obesity is provided which comprisesthe step of administering to a subject in need of such treatment aneffective amount of a composition comprising at least one sterolabsorption inhibitor represented by Formula (II) below:

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified in all instances by the term “about.”

DETAILED DESCRIPTION

In one embodiment, the present invention is directed to compositions,pharmaceutical compositions, therapeutic combinations, kits and methodsof treatment using the same comprising (1) at least one (one or more)obesity control medication(s); and (2) at least one (one or more) sterolabsorption inhibitor(s) and/or at least one (one or more) 5α-stanolabsorption inhibitor(s), such as but not limited to, substitutedazetidinone sterol absorption inhibitors or substituted β-lactam sterolabsorption inhibitors discussed in detail below.

Many different agents are useful for the control or medical managementof obesity. The different agents can be classified by their mechanism ofaction, such as but not limited to, drugs that reduce energy intake orsuppress appetite, drugs that increase energy expenditure andnutrient-partitioning agents.

Drugs that reduce energy intake include, in part, variouspharmacological agents, referred to as anorectic drugs, which are usedas adjuncts to behavioral therapy in weight reduction programs. Classesof anorectic drugs include, but are not limited to, noradrenergic andserotonergic agents. Noradrenergic medications may be described as thosemedications generally preserving the anorectic effects of amphetaminesbut with weaker stimulant activity. The noradrenergic drugs, exceptphenylpropanolamine, generally act through a centrally mediated pathwayin the hypothalamus that causes anorexia. Phenylpropanolamine, a racemicmixture of norephedrine esters, causes a release of norepinephrinethroughout the body and stimulates hypothalamic adrenoreceptors toreduce appetite.

Suitable noradrenergic agents include, but are not limited to,diethylpropion such as TENUATE® (1-propanone,2-(diethylamino)—1-phenyl-, hydrochloride) commercially available fromMerrell; mazindol (or5-(p-chlorophenyl)—2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol) such asSANOREX® commercially available from Novartis or MAZANOR® commerciallyavailable from Wyeth Ayerst; phenylpropanolamine (or Benzenemethanol,alpha-(1-aminoethyl)—, hydrochloride); phentermine (or Phenol,3-[[4,5-duhydro-1H-imidazol-2-yl)ethyl](4-methylphenyl)amino],monohydrochloride) such as ADIPEX-P® commercially available from Lemmon,FASTIN® commercially available from Smith-Kline Beecham and Ionamin®commercially available from Medeva; phendimetrazine (or(2S,3S)—3,4-Dimethyl-2phenylmorpholine L-(+)—tartrate (1:1)) such asMETRA® commercially available from Forest, PLEGINE® commerciallyavailable from Wyeth-Ayerst; PRELU-2® commercially available fromBoehringer Ingelheim, and STATOBEX® commercially available from Lemmon;phendamine tartrate such as THEPHORIN®(2,3,4,9-Tetrahydro-2-methyl-9-phenyl-1H-indenol[2,1-c]pyridineL-(+)—tartrate (1:1)) commercially available from Hoffmann-LaRoche;methamphetamine such as DESOXYN® Tablets ((S)—N,(alpha)—dimethylbenzeneethanamine hydrochloride) commercially availablefrom Abbott; and phendimetrazine tartrate such as BONTRIL® Slow-ReleaseCapsules (-3,4-Dimethyl-2-phenylmorpholine Tartrate) commerciallyavailable from Amarin.

Suitable non-limiting serotonergic agents include sibutramine such asMERIDIA® Capsules (a racemic mixture of the (+) and (−) enantiomers ofcyclobutanemethanamine,1-(4-chlorophenyl)—N,N-dimethyl-(alpha)—(2-methylpropyl)—,hydrochloride, monohydrate) commercially available from Knoll,fenfluramine such as Pondimin® (Benzeneethanamine,N-ethyl-alpha-methyl-3-(trifluoromethyl)—, hydrochloride) commerciallyavailable from Robbins; dexfenfluramine such as Redux®(Benzeneethanamine, N-ethyl-alpha-methyl-3-(trifluoromethyl)—,hydrochloride) commercially available from Interneuron. Fenfluramine anddexfenfluramine stimulate release of serotonin and inhibit its reuptake.Sibutramine inhibits the reuptake of serotonin, norepinephrine anddopamine, but does not stimulate secretion of serotonin.

Other serotonergic agents useful with the practice of the presentinvention include, but are not limited to, certain auoretic gene 5HT1ainhibitors (brain, serotonin) such as carbidopa and benserazide asdisclosed by U.S. Pat. No. 6,207,699 which is incorporated herein byreference; and certain neurokinin 1 receptor antagonist and selectiveserotonin reuptake inhibitors including fluoxetine, fluvoxamine,paroxtine, sertraline and other useful compounds as disclosed by U.S.Pat. No. 6,162,805 which is incorporated herein by reference.

Other useful compounds for reducing energy intake include, but are notlimited to, certain aryl-substituted cyclobutylalkylamines as disclosedby U.S. Pat. No. 6,127,424 which is incorporated herein by reference;certain trifluoromethylthiophenylethylamine derivatives as disclosed byU.S. Pat. No. 4,148,923 which is incorporated herein by reference;certain compounds as disclosed by U.S. Pat. No. 6,207,699 which isincorporated herein by reference; certain kainite or AMPA receptorantagonists as disclosed by U.S. Pat. No. 6,191,117 which isincorporated herein by reference; certain neuropeptide receptor subtype5 as disclosed by U.S. Pat. No. 6,140,354 which is incorporated hereinby reference; and certain alpha-blocking agents as disclosed by U.S.Pat. No. 4,239,763 which is incorporated herein by reference.

Moreover, several peptides and hormones regulate feeding behavior. Forexample, cholecystokinin and serotonin act to decrease appetite and foodintake. Leptin, a hormone produced by fat cells, controls food intakeand energy expenditure. In obese persons who are losing weight withoutmedications, a decrease in weight is associated with a decrease incirculating levels of leptin, suggesting its role in weight homeostasis.Obese patients with high leptin levels are thought to have peripheralleptin resistance secondary to the down-regulation of leptin receptors.Non-limiting examples of useful compounds affecting feeding behaviorinclude certain leptin-lipolysis stimulated receptors as disclosed by WO01/21647 which is incorporated herein by reference; certainphosphodiesterase enzyme inhibitors as disclosed by WO 01/35970 which isincorporated herein by reference; certain compounds having nucleotidesequences of the mahogany gene as disclosed by WO 00/05373 which isincorporated herein by reference; certain sapogenin compounds asdisclosed by U.S. Pat. No. 4,680,289 which is incorporated herein byreference.

Other useful compounds include certain gamma peroxisome proliferatoractivated receptor (PPAR) agonists as disclosed by WO 01/30343 and U.S.Pat. No. 6,033,656 which are incorporated herein by reference andcertain polypeptides such as fibroblast growth factor-10 polypeptides asdisclosed by WO 01/18210 which is incorporated herein by reference.

Moreover, monoamine oxidase inhibitors that decrease energy intake orincrease energy expenditure are useful with the practice of the presentinvention. Suitable, but non-limiting examples of monoamine oxidaseinhibitors include befloxatone, moclobemide, brofaromine, phenoxathine,esuprone, befol, toloxatone, pirlindol, amiflamine, sercloremine,bazinaprine, lazabemide, milacemide, caroxazone and other certaincompounds as disclosed by WO 01/12176 which is incorporated herein byreference.

Certain compounds that increase lipid metabolism are also useful withthe practice of the present invention. Such compounds include, but arenot limited to, useful evodiamine compounds as disclosed by U.S. Pat.No. 6,214,831 which is incorporated herein by reference.

Nutrient partitioning agents and digestive inhibitors are anotherstrategy in the treatment of obesity by interfering with the breakdown,digestion or absorption of dietary fat in the gastrointestinal tract.Gastric and pancreatic lipases aid in the digestion of dietarytriglycerides by forming them into free fatty acids that are thenabsorbed in the small intestine. Inhibition of these enzymes leads toinhibition of the digestion of dietary triglycerides. Non-limitingexamples include a lipase inhibitor, orlistat, such as XENICAL® Capsules((S)—2-formylamino-4-methyl-pentanoic acid(S)—1-[[(2S,3S)—3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl ester)commercially available from Roche Laboratories and certain benzoxazinonecompounds as described by WO 00/40247 which is incorporated herein byreference.

Agents that increase energy expenditure are also referred to asthermogenic medications. Non-limiting examples of suitable thermogenicmedications include ephedrine, and xanthines, such as caffeine andtheophylline, selective β3-adrenergic agonists for example certaincompounds in U.S. Pat. No. 4,626,549 which is incorporated by referenceherein, α-2-adrenergic and growth hormones compounds as described inU.S. Pat. Nos. 4,937,267 and 5,120,713 which are incorporated byreference herein; and suitable herbal extracts such as Thermo-E Capletscommercially available from AdvoCare which contains ephedra.

Generally, a total dosage of the above-described obesity control agentsor medications can range from 1 to 3,000 mg/day, preferably from about 1to 1,000 mg/day and more preferably from about 1 to 200 mg/day in singleor 2–4 divided doses. The exact dose, however, is determined by theattending clinician and is dependent on such factors as the potency ofthe compound administered, the age, weight, condition and response ofthe patient.

The term “therapeutically effective amount” means that amount of atherapeutic agent of the composition, such as the obesity controlmedication, sterol or 5α-stanol absorption inhibitor(s) and otherpharmacological or therapeutic agents described below, that will elicita biological or medical response of a tissue, system, or subject that isbeing sought by the administrator (such as a researcher, doctor orveterinarian) which includes alleviation of the symptoms of thecondition or disease being treated and the prevention, slowing orhalting of progression of the condition (such as obesity or a vascularcondition). As used herein, “vascular” means relating to blood vessels,including but not limited to arteries and/or veins, and includescardiovascular, cerebrovascular, peripheral vascular and combinationsthereof.

Examples of suitable subjects that can be treated according to themethods of the present invention include mammals, such as humans ordogs, and other animals.

As used herein, “combination therapy” or “therapeutic combination” meansthe administration of two or more therapeutic agents, such as obesitycontrol medication and sterol and/or 5α-stanol absorption inhibitor(s),to prevent or treat obesity. Such administration includescoadministration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single tablet or capsule having afixed ratio of active ingredients or in multiple, separate capsules foreach therapeutic agent. Also, such administration includes use of eachtype of therapeutic agent in a sequential manner. In either case, thetreatment using the combination therapy will provide beneficial effectsin treating obesity. A potential advantage of the combination therapydisclosed herein may be a reduction in the required amount of anindividual therapeutic compound or the overall total amount oftherapeutic compounds that are effective in treating obesity. By using acombination of therapeutic agents, the side effects of the individualcompounds can be reduced as compared to a monotherapy, which can improvepatient compliance. Also, therapeutic agents can be selected to providea broader range of complimentary effects or complimentary modes ofaction.

As discussed above, in one embodiment, the compositions, pharmaceuticalcompositions and therapeutic combinations of the present invention cancomprise one or more sterol or 5α-stanol absorption inhibitors, forexample substituted azetidinone sterol absorption inhibitors orsubstituted β-lactam sterol absorption inhibitors discussed in detailbelow. As used herein, “sterol absorption inhibitor” means a compoundcapable of inhibiting the absorption of one or more sterols, includingbut not limited to cholesterol or phytosterols (such as sitosterol,campesterol, stigmasterol and avenosterol) when administered in atherapeutically effective (sterol absorption inhibiting) amount to asubject. “5α-stanol absorption inhibitor” means a compound capable ofinhibiting the absorption of one or more 5α-stanols (such ascholestanol, 5α-campestanol, 5α-sitostanol) when administered in atherapeutically effective (5α-stanol absorption inhibiting) amount to asubject. Mixtures of sterol absorption inhibitor(s) and 5α-stanolabsorption inhibitor(s) are contemplated.

In a preferred embodiment, sterol and/or 5α-stanol absorption inhibitorsuseful in the compositions, therapeutic combinations and methods of thepresent invention are represented by Formula (I) below:

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (I) above:

Ar¹ and Ar² are independently selected from the group consisting of aryland R⁴-substituted aryl;

Ar³ is aryl or R⁵-substituted aryl;

X, Y and Z are independently selected from the group consisting of—CH₂—, —CH(lower alkyl)—and —C(dilower alkyl)—;

R and R² are independently selected from the group consisting of —OR⁶,—O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷;

R¹ and R³ are independently selected from the group consisting ofhydrogen, lower alkyl and aryl;

q is 0 or 1; r is 0 or 1; m, n and p are independently selected from 0,1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum ofm, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;

R⁴ is 1–5 substituents independently selected from the group consistingof lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —(lower alkylene)COOR⁶, —CH═CH—COOR⁶, —CF₃, —CN,—NO₂ and halogen;

R⁵ is 1–5 substituents independently selected from the group consistingof —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷,—NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷,—COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷,—(lower alkylene)COOR⁶ and —CH═CH—COOR⁶;

R⁶, R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.

Preferably, R⁴ is 1–3 independently selected substituents, and R⁵ ispreferably 1–3 independently selected substituents.

As used herein, the term “alkyl” or “lower alkyl” means straight orbranched alkyl chains having from 1 to 6 carbon atoms and “alkoxy” meansalkoxy groups having 1 to 6 carbon atoms. Non-limiting examples of loweralkyl groups include, for example methyl, ethyl, propyl, and butylgroups.

“Alkenyl” means straight or branched carbon chains having one or moredouble bonds in the chain, conjugated or unconjugated. Similarly,“alkynyl” means straight or branched carbon chains having one or moretriple bonds in the chain. Where an alkyl, alkenyl or alkynyl chainjoins two other variables and is therefore bivalent, the terms alkylene,alkenylene and alkynylene are used.

“Cycloalkyl” means a saturated carbon ring of 3 to 6 carbon atoms, while“cycloalkylene” refers to a corresponding bivalent ring, wherein thepoints of attachment to other groups include all positional isomers.

“Halogeno” refers to fluorine, chlorine, bromine or iodine radicals.

“Aryl” means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.

“Phenylene” means a bivalent phenyl group, including ortho, meta andpara-substitution.

The statements wherein, for example, R, R¹, R² and R³, are said to beindependently selected from a group of substituents, mean that R, R¹, R²and R³ are independently selected, but also that where an R, R¹, R² andR³ variable occurs more than once in a molecule, each occurrence isindependently selected (e.g., if R is —OR⁶, wherein R⁶ is hydrogen, R²can be —OR⁶ wherein R⁶ is lower alkyl). Those skilled in the art willrecognize that the size and nature of the substituent(s) will affect thenumber of substituents that can be present. Compounds of the inventionhave at least one asymmetrical carbon atom and therefore all isomers,including enantiomers, stereoisomers, rotamers, tautomers and racematesof the compounds of Formulae I–XII are contemplated as being part ofthis invention. The invention includes d and l isomers in both pure formand in admixture, including racemic mixtures. Isomers can be preparedusing conventional techniques, either by reacting optically pure oroptically enriched starting materials or by separating isomers of acompound of the Formulas I–XII. Isomers may also include geometricisomers, e.g., when a double bond is present.

Those skilled in the art will appreciate that for some of the compoundsof the Formulas I–XII, one isomer will show greater pharmacologicalactivity than other isomers.

Compounds of the invention with an amino group can form pharmaceuticallyacceptable salts with organic and inorganic acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,maleic, methanesulfonic and other mineral and carboxylic acids wellknown to those in the art. The salt is prepared by contacting the freebase form with a sufficient amount of the desired acid to produce asalt. The free base form may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous sodiumbicarbonate. The free base form differs from its respective salt formsomewhat in certain physical properties, such as solubility in polarsolvents, but the salt is otherwise equivalent to its respective freebase forms for purposes of the invention.

Certain compounds of the invention are acidic (e.g., those compoundswhich possess a carboxyl group). These compounds form pharmaceuticallyacceptable salts with inorganic and organic bases. Examples of suchsalts are the sodium, potassium, calcium, aluminum, gold and silversalts. Also included are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

As used herein, “solvate” means a molecular or ionic complex ofmolecules or ions of solvent with those of solute (for example, one ormore compounds of Formulae I–XII, isomers of the compounds of FormulaeI–XII, or prodrugs of the compounds of Formulae I–XII). Non-limitingexamples of useful solvents include polar, protic solvents such as waterand/or alcohols (for example methanol).

Prodrugs of the compounds of Formulae I–XII are contemplated as beingpart of this invention. As used herein, “prodrug” means compounds thatare drug precursors which, following administration to a patient,release the drug in vivo via some chemical or physiological process(e.g., a prodrug on being brought to the physiological pH or throughenzyme action is converted to the desired drug form).

Preferred compounds of Formula (I) are those in which Ar¹ is phenyl orR⁴-substituted phenyl, more preferably (4-R⁴)—substituted phenyl. Ar² ispreferably phenyl or R⁴-substituted phenyl, more preferably(4-R⁴)—substituted phenyl. Ar³ is preferably R⁵-substituted phenyl, morepreferably (4-R⁵)—substituted phenyl. When Ar¹ is (4-R⁴)—substitutedphenyl, R⁴ is preferably a halogen. When Ar² and Ar³ are R⁴- andR⁵-substituted phenyl, respectively, R⁴ is preferably halogen or —OR⁶and R⁵ is preferably —OR⁶, wherein R⁶ is lower alkyl or hydrogen.Especially preferred are compounds wherein each of Ar¹ and Ar² is4-fluorophenyl and Ar³ is 4-hydroxyphenyl or 4-methoxyphenyl.

X, Y and Z are each preferably —CH₂—. R¹ and R³ are each preferablyhydrogen. R and R² are preferably —OR⁶ wherein R⁶ is hydrogen, or agroup readily metabolizable to a hydroxyl (such as —O(CO)R⁶, —O(CO)OR⁹and —O(CO)NR⁶R⁷, defined above).

The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3.Preferred are compounds wherein m, n and r are each zero, q is 1 and pis 2.

Also preferred are compounds of Formula (I) in which p, q and n are eachzero, r is 1 and m is 2 or 3. More preferred are compounds wherein m, nand r are each zero, q is 1, p is 2, Z is —CH₂— and R is —OR⁶,especially when R⁶ is hydrogen.

Also more preferred are compounds of Formula (I) wherein p, q and n areeach zero, r is 1, m is 2, X is —CH₂— and R² is —OR⁶, especially when R⁶is hydrogen.

Another group of preferred compounds of Formula (I) is that in which Ar¹is phenyl or R⁴-substituted phenyl, Ar² is phenyl or R⁴-substitutedphenyl and Ar³ is R⁵-substituted phenyl. Also preferred are compounds inwhich Ar¹ is phenyl or R⁴-substituted phenyl, Ar² is phenyl orR⁴-substituted phenyl, Ar³ is R⁵-substituted phenyl, and the sum of m,n, p, q and r is 2, 3 or 4, more preferably 3. More preferred arecompounds wherein Ar¹ is phenyl or R⁴-substituted phenyl, Ar² is phenylor R⁴-substituted phenyl, Ar³ is R⁵-substituted phenyl, and wherein m, nand r are each zero, q is 1 and p is 2, or wherein p, q and n are eachzero, r is 1 and m is 2 or 3.

In a preferred embodiment, a sterol or 5α-stanol absorption inhibitor ofFormula (I) useful in the compositions, therapeutic combinations andmethods of the present invention is represented by Formula (II)(ezetimibe) below:

or a pharmaceutically acceptable salt or solvate thereof. The compoundof Formula (II) can be in anhydrous or hydrated form.

Compounds of Formula I can be prepared by a variety of methods wellknown to those skilled in the art, for example such as are disclosed inU.S. Pat. Nos. 5,631,365, 5,767,115, 5,846,966, 6,207,822, U.S. patentapplication Ser. No. 10/105,710 filed Mar. 25, 2002 and PCT PatentApplication WO 93/02048, each of which is incorporated herein byreference, and in the Example below. For example, suitable compounds ofFormula I can be prepared by a method comprising the steps of:

(a) treating with a strong base a lactone of the Formula A or B:

wherein R′ and R²′ are R and R², respectively, or are suitably protectedhydroxy groups; Ar¹⁰ is Ar¹, a suitably protected hydroxy-substitutedaryl or a suitably protected amino-substituted aryl; and the remainingvariables are as defined above for Formula I, provided that in lactoneof formula B, when n and r are each zero, p is 1–4;

(b) reacting the product of step (a) with an imine of the formula

wherein Ar²⁰ is Ar², a suitably protected hydroxy-substituted aryl or asuitably protected amino-substituted aryl; and Ar³⁰ is Ar³, a suitablyprotected hydroxy-substituted aryl or a suitably protectedamino-substituted aryl;

c) quenching the reaction with an acid;

d) optionally removing the protecting groups from R′, R²′, Ar¹⁰, Ar²⁰and Ar³⁰, when present; and

e) optionally functionalizing hydroxy or amino substituents at R, R²,Ar¹, Ar² and Ar³.

Using the lactones shown above, compounds of Formula IA and IB areobtained as follows:

wherein the variables are as defined above; and

wherein the variables are as defined above.

Alternative sterol or 5α-stanol absorption inhibitors useful in thecompositions, therapeutic combinations and methods of the presentinvention are represented by Formula (III) below:

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (III) above:

Ar¹ is R³-substituted aryl;

Ar² is R⁴-substituted aryl;

Ar³ is R⁵-substituted aryl;

Y and Z are independently selected from the group consisting of —CH₂—,—CH(lower alkyl)—and —C(dilower alkyl)—;

A is selected from —O—, —S—, —S(O)— or —S(O)₂—;

R¹ is selected from the group consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹and —O(CO)NR⁶R⁷; R² is selected from the group consisting of hydrogen,lower alkyl and aryl; or R¹ and R² together are ═O;

q is 1, 2 or 3;

p is 0, 1, 2, 3 or 4;

R⁵ is 1–3 substituents independently selected from the group consistingof —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁹, —O(CO)NR⁶R⁷, —NR⁶R⁷,—NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂-lower alkyl,—NR⁶SO₂-aryl, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂-alkyl, S(O)₀₋₂-aryl,—O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, o-halogeno, m-halogeno, o-loweralkyl, m-lower alkyl, —(lower alkylene)—COOR⁶, and —CH═CH—COOR⁶;

R³ and R⁴ are independently 1–3 substituents independently selected fromthe group consisting of R⁵, hydrogen, p-lower alkyl, aryl, —NO₂, —CF₃and p-halogeno;

R⁶, R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R⁹ islower alkyl, aryl or aryl-substituted lower alkyl.

Preferred compounds of Formula I include those in which Ar¹ isR³-substituted phenyl, especially (4-R³)—substituted phenyl. Ar² ispreferably R⁴-substituted phenyl, especially (4-R⁴)—substituted phenyl.Ar³ is preferably R⁵-substitiuted phenyl, especially (4-R⁵)—substitutedphenyl. Mono-substitution of each of Ar¹, Ar² and Ar³ is preferred.

Y and Z are each preferably —CH₂—. R² is preferably hydrogen. R¹ ispreferably —OR⁶ wherein R⁶ is hydrogen, or a group readily metabolizableto a hydroxyl (such as —O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷, definedabove). Also preferred are compounds wherein R¹ and R² together are ═O.

The sum of q and p is preferably 1 or 2, more preferably 1. Preferredare compounds wherein p is zero and q is 1. More preferred are compoundswherein p is zero, q is 1, Y is —CH₂— and R¹ is —OR⁶, especially when R⁶is hydrogen.

Another group of preferred compounds is that in which Ar¹ isR³-substituted phenyl, Ar² is R⁴-substituted phenyl and Ar³ isR⁵-substituted phenyl.

Also preferred are compounds wherein Ar¹ is R³-substituted phenyl, Ar²is R⁴-substituted phenyl, Ar³ is R⁵-substituted phenyl, and the sum of pand q is 1 or 2, especially 1. More preferred are compounds wherein Ar¹is R³-substituted phenyl, Ar² is R⁴-substituted phenyl, Ar³ isR⁵-substituted phenyl, p is zero and q is 1.

A is preferably —O—.

R³ is preferably —COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂-alkyl,S(O)₀₋₂-aryl, NO₂ or halogeno. A more preferred definition for R³ ishalogeno, especially fluoro or chloro.

R⁴ is preferably hydrogen, lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CO)NR⁶R⁷, —NR⁶R⁷, COR⁶ or halogeno, wherein R⁶ and R⁷ are preferablyindependently hydrogen or lower alkyl, and R⁹ is preferably lower alkyl.A more preferred definition for R⁴ is hydrogen or halogeno, especiallyfluoro or chloro.

R⁵ is preferably —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CO)NR⁶R⁷, —NR⁶R⁷, —(loweralkylene)—COOR⁶ or —CH═CH—COOR⁶, wherein R⁶ and R⁷ are preferablyindependently hydrogen or lower alkyl, and R⁹ is preferably lower alkyl.A more preferred definition for R⁵ is —OR⁶, —(lower alkylene)—COOR⁶ or—CH═CH—COOR⁶, wherein R⁶ is preferably hydrogen or lower alkyl.

Methods for making compounds of Formula III are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,688,990, which is incorporated herein byreference.

In another embodiment, sterol or 5α-stanol absorption inhibitors usefulin the compositions, therapeutic combinations and methods of the presentinvention are represented by Formula (IV):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (IV) above:

A is selected from the group consisting of R²-substitutedheterocycloalkyl, R²-substituted heteroaryl, R²-substituted benzofusedheterocycloalkyl, and R²-substituted benzofused heteroaryl;

Ar¹ is aryl or R³-substituted aryl;

Ar² is aryl or R⁴-substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone,forms the spiro group

R¹ is selected from the group consisting of:

-   -   —(CH₂)_(q)—, wherein q is 2–6, provided that when Q forms a        spiro ring, q can also be zero or 1;    -   —(CH₂)_(e)—G—(CH₂)_(r)—, wherein G is —O—, —C(O)—, phenylene,        —NR⁸— or —S(O)₀₋₂—, e is 0–5 and r is 0–5, provided that the sum        of e and r is 1–6;    -   —(C₂–C₆ alkenylene)—; and    -   —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃–C₆ cycloalkylene, f is        1–5 and g is 0–5, provided that the sum of f and g is 1–6;

R⁵ is selected from:

R⁶ and R⁷ are independently selected from the group consisting of —CH₂—,—CH(C₁–C₆ alkyl)—, —C(di-(C₁–C₆)alkyl), —CH═CH— and —C(C₁–C₆ alkyl)═CH—;or R⁵ together with an adjacent R⁶, or R⁵ together with an adjacent R⁷,form a —CH═CH— or a —CH═C(C₁–C₆ alkyl)—group;

a and b are independently 0, 1, 2 or 3, provided both are not zero;provided that when R⁶ is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, a is 1;provided that when R⁷ is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, b is 1;provided that when a is 2 or 3, the R⁶'s can be the same or different;and provided that when b is 2 or 3, the R⁷'s can be the same ordifferent;

and when Q is a bond, R¹ also can be selected from:

where M is —O—, —S—, —S(O)— or —S(O)₂—;

X, Y and Z are independently selected from the group consisting of—CH₂—, —CH(C₁–C₆ alkyl)—and —C(di-(C₁–C₆)alkyl);

R¹⁰ and R¹² are independently selected from the group consisting of—OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶ and —O(CO)NR¹⁴R¹⁵;

R¹¹ and R¹³ are independently selected from the group consisting ofhydrogen, (C₁–C₆)alkyl and aryl; or R¹⁰ and R¹¹ together are ═O, or R¹²and R¹³ together are ═O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1; t is 0 or 1; m, n and p are independently 0–4; providedthat at least one of s and t is 1, and the sum of m, n, p, s and t is1–6; provided that when p is 0 and t is 1, the sum of m, s and n is 1–5;and provided that when p is 0 and s is 1, the sum of m, t and n is 1–5;

v is 0 or 1;

j and k are independently 1–5, provided that the sum of j, k and v is1–5;

R² is 1–3 substituents on the ring carbon atoms selected from the groupconsisting of hydrogen, (C₁–C₁₀)alkyl, (C₂–C₁₀)alkenyl, (C₂–C₁₀)alkynyl,(C₃–C₆)cycloalkyl, (C₃–C₆)cycloalkenyl, R¹⁷-substituted aryl,R¹⁷-substituted benzyl, R¹⁷-substituted benzyloxy, R¹⁷-substitutedaryloxy, halogeno, —NR¹⁴R¹⁵, NR¹⁴R¹⁵(C₁–C₆ alkylene)—, NR¹⁴R¹⁵C(O)(C₁–C₆alkylene)—, —NHC(O)R¹⁶, OH, C₁–C₆ alkoxy, —OC(O)R¹⁶, —COR¹⁴,hydroxy(C₁–C₆)alkyl, (C₁–C₆)alkoxy(C₁–C₆)alkyl, NO₂, —S(O)₀₋₂R¹⁶,—SO₂NR¹⁴R¹⁵ and —(C₁–C₆ alkylene)COOR¹⁴; when R² is a substituent on aheterocycloalkyl ring, R² is as defined, or is ═O or

and, where R² is a substituent on a substitutable ring nitrogen, it ishydrogen, (C₁–C₆)alkyl, aryl, (C₁–C₆)alkoxy, aryloxy,(C₁–C₆)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH₂)₁₋₆CONR¹⁸R¹⁸,

wherein J is —O—, —NH—, —NR¹⁸— or —CH₂—;

R³ and R⁴ are independently selected from the group consisting of 1–3substituents independently selected from the group consisting of(C₁–C₆)alkyl, —OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶, —O(CH₂)₁₋₅OR¹⁴,—O(CO)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴(CO)R¹⁵, —NR¹⁴(CO)OR¹⁶, —NR¹⁴(CO)NR¹⁵R¹⁹,—NR¹⁴SO₂R¹⁶, —COOR¹⁴, —CONR¹⁴R¹⁵, —COR¹⁴, —SO₂NR¹⁴R¹⁵, S(O)₀₋₂R¹⁶,—O(CH₂)₁₋₁₀—COOR¹⁴, —O(CH₂)₁₋₁₀CONR¹⁴R¹⁵, —(C₁–C₆ alkylene)—COOR¹⁴,—CH═CH—COOR¹⁴, —CF₃, —CN, —NO₂ and halogen;

R⁸ is hydrogen, (C₁–C₆)alkyl, aryl (C₁–C₆)alkyl, —C(O)R¹⁴ or —COOR¹⁴;

R⁹ and R¹⁷ are independently 1–3 groups independently selected from thegroup consisting of hydrogen, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, —COOH, NO₂,—NR¹⁴R¹⁵, OH and halogeno;

R¹⁴ and R¹⁵ are independently selected from the group consisting ofhydrogen, (C₁–C₆)alkyl, aryl and aryl-substituted (C₁–C₆)alkyl;

R¹⁶ is (C₁–C₆)alkyl, aryl or R¹⁷-substituted aryl;

R¹⁸ is hydrogen or (C₁–C₆)alkyl; and

R¹⁹ is hydrogen, hydroxy or (C₁–C₆)alkoxy.

As used in Formula (IV) above, “A” is preferably an R²-substituted,6-membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms.Preferred heterocycloalkyl rings are piperidinyl, piperazinyl andmorpholinyl groups. The ring “A” is preferably joined to the phenyl ringthrough a ring nitrogen. Preferred R² substituents are hydrogen andlower alkyl. R¹⁹ is preferably hydrogen.

Ar² is preferably phenyl or R⁴-phenyl, especially (4-R⁴)—substitutedphenyl. Preferred definitions of R⁴ are lower alkoxy, especiallymethoxy, and halogeno, especially fluoro.

Ar¹ is preferably phenyl or R³-substituted phenyl, especially(4-R³)—substituted phenyl.

There are several preferred definitions for the —R¹—Q—combination ofvariables:

Q is a bond and R¹ is lower alkylene, preferably propylene;

Q is a spiro group as defined above, wherein preferably R⁶ and R⁷ areeach ethylene and R⁵ is

Q is a bond and R¹ is

wherein the variables are chosen such that R¹ is —O—CH₂—CH(OH)—;

Q is a bond and R¹ is

wherein the variables are chosen such that R¹ is —CH(OH)—(CH₂)₂—; and

Q is a bond and R¹ is

wherein the variables are chosen such that R¹ is —CH(OH)—CH₂—S(O)₀₋₂—.

Methods for making compounds of Formula IV are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,656,624, which is incorporated herein byreference.

In another embodiment, sterol or 5α-stanol absorption inhibitors usefulin the compositions, therapeutic combinations and methods of the presentinvention are represented by Formula (V):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (V) above:

Ar¹ is aryl, R¹⁰-substituted aryl or heteroaryl;

Ar² is aryl or R⁴-substituted aryl;

Ar³ is aryl or R⁵-substituted aryl;

X and Y are independently selected from the group consisting of —CH₂—,—CH(lower alkyl)— and —C(dilower alkyl)—;

R is —OR⁶, —O(CO)R⁶, —O(CO)OR⁹ or —O(CO)NR⁶R⁷; R¹ is hydrogen, loweralkyl or aryl; or R and R¹ together are ═O;

q is 0 or 1;

r is 0, 1 or 2;

m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum ofm, n and q is 1, 2, 3, 4 or 5;

R⁴ is 1–5 substituents independently selected from the group consistingof lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —(lower alkylene)COOR⁶ and —CH═CH—COOR⁶;

R⁵ is 1–5 substituents independently selected from the group consistingof —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷,—NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶—CONR⁶R⁷,—COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷,—CF₃, —CN, —NO₂, halogen, —(lower alkylene)COOR⁶ and —CH═CH—COOR⁶;

R⁶, R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and

R¹⁰ is 1–5 substituents independently selected from the group consistingof lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, —S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂ and halogen.

Within the scope of Formula V, there are included two preferredstructures. In Formula VA, q is zero and the remaining variables are asdefined above, and in Formula VB, q is 1 and the remaining variables areas defined above:

R⁴, R⁵ and R¹⁰ are each preferably 1–3 independently selectedsubstituents as set forth above. Preferred are compounds of Formula (V)wherein Ar¹ is phenyl, R¹⁰-substituted phenyl or thienyl, especially(4-R¹⁰)—substituted phenyl or thienyl. Ar² is preferably R⁴-substitutedphenyl, especially (4-R⁴)—substituted phenyl. Ar³ is preferably phenylor R⁵-substituted phenyl, especially (4-R⁵)—substituted phenyl. When Ar¹is R¹⁰-substituted phenyl, R¹⁰ is preferably halogeno, especiallyfluoro. When Ar² is R⁴-substituted phenyl, R⁴ is preferably —OR⁶,especially wherein R⁶ is hydrogen or lower alkyl. When Ar³ isR⁵-substituted phenyl, R⁵ is preferably halogeno, especially fluoro.Especially preferred are compounds of Formula (V) wherein Ar¹ is phenyl,4-fluorophenyl or thienyl, Ar² is 4—(alkoxy or hydroxy)phenyl, and Ar³is phenyl or 4-fluorophenyl.

X and Y are each preferably —CH₂—. The sum of m, n and q is preferably2, 3 or 4, more preferably 2. When q is 1, n is preferably 1 to 5.

Preferences for X, Y, Ar¹, Ar² and Ar³ are the same in each of Formulae(VA) and (VB).

In compounds of Formula (VA), the sum of m and n is preferably 2, 3 or4, more preferably 2. Also preferred are compounds wherein the sum of mand n is 2, and r is 0 or 1.

In compounds of Formula (VB), the sum of m and n is preferably 1, 2 or3, more preferably 1. Especially preferred are compounds wherein m iszero and n is 1. R¹ is preferably hydrogen and R is preferably —OR⁶wherein R⁶ is hydrogen, or a group readily metabolizable to a hydroxyl(such as —O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷, defined above), or R andR¹ together form a ═O group.

Methods for making compounds of Formula V are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,624,920, which is incorporated herein byreference.

In another embodiment, sterol or 5α-stanol absorption inhibitors usefulin the compositions, therapeutic combinations and methods of the presentinvention are represented by Formula (VI):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein:

R₁ is

R₂ and R₃ are independently selected from the group consisting of:—CH₂—, —CH(lower alkyl)—, —C(di-lower alkyl)—, —CH═CH— and —C(loweralkyl)═CH—; or R₁ together with an adjacent R₂, or R₁ together with anadjacent R₃, form a —CH═CH— or a —CH═C(lower alkyl)—group;

u and v are independently 0, 1, 2 or 3, provided both are not zero;provided that when R₂ is —CH═CH— or —C(lower alkyl)═CH—, v is 1;provided that when R₃ is —CH═CH— or —C(lower alkyl)═CH—, u is 1;provided that when v is 2 or 3, the R₂'s can be the same or different;and provided that when u is 2 or 3, the R₃'s can be the same ordifferent;

R₄ is selected from B—(CH₂)_(m)C(O)—, wherein m is 0, 1, 2, 3, 4 or 5;B—(CH₂)_(q)—, wherein q is 0, 1, 2, 3, 4, 5 or 6;B—(CH₂)_(e)—Z—(CH₂)_(r)—, wherein Z is —O—, —C(O)—, phenylene, —N(R₈)—or —S(O)₀₋₂—, e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5,provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6; B—(C₂–C₆alkenylene)—; B—(C₄–C₆ alkadienylene)—; B—(CH₂)_(t)—Z—(C₂–C₆alkenylene)—, wherein Z is as defined above, and wherein t is 0, 1, 2 or3, provided that the sum of t and the number of carbon atoms in thealkenylene chain is 2, 3, 4, 5 or 6; B—(CH₂)_(f)—V—(CH₂)_(g)—, wherein Vis C₃–C₆ cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;B—(CH₂)_(t)—V—(C₂–C₆ alkenylene)—or B—(C2–C6 alkenylene)—V—(CH₂)_(t)—,wherein V and t are as defined above, provided that the sum of t and thenumber of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;B—(CH₂)_(a)—Z—(CH₂)_(b)—V—(CH₂)_(d)—, wherein Z and V are as definedabove and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, providedthat the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or T—(CH₂)_(s)—,wherein T is cycloalkyl of 3–6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or6; or

R₁ and R₄ together form the group

B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selectedfrom the group consisting of pyrrolyl, pyridinyl, pyrimidinyl,pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl,oxazolyl and furanyl, and for nitrogen-containing heteroaryls, theN-oxides thereof, or

W is 1 to 3 substituents independently selected from the groupconsisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (loweralkoxyimino)—lower alkyl, lower alkanedioyl, lower alkyl loweralkanedioyl, allyloxy, —CF₃, —OCF₃, benzyl, R₇-benzyl, benzyloxy,R₇-benzyloxy, phenoxy, R₇-phenoxy, dioxolanyl, NO₂, —N(R₈)(R₉),N(R₈)(R₉)—lower alkylene—, N(R₈)(R₉)—lower alkylenyloxy—, OH, halogeno,—CN, —N₃, —NHC(O)OR₁₀, —NHC(O)R₁₀, R₁₁O₂SNH—, (R₁₁O₂S)₂N—, —S(O)₂NH₂,—S(O)₀₋₂R₈, tert-butyldimethyl-silyloxymethyl, —C(O)R₁₂, —COOR₁₉,—CON(R₈)(R₉), —CH═CHC(O)R₁₂, —lower alkylene—C(O)R₁₂, R₁₀C(O)(loweralkylenyloxy)—, N(R₈)(R₉)C(O)(lower alkylenyloxy)—and

for substitution on ring carbon atoms, and the substituents on thesubstituted heteroaryl ring nitrogen atoms, when present, are selectedfrom the group consisting of lower alkyl, lower alkoxy, —C(O)OR₁₀,—C(O)R₁₀, OH, N(R₈)(R₉)—lower alkylene—, N(R₈)(R₉)—lower alkylenyloxy—,—S(O)₂NH₂ and 2—(trimethylsilyl)—ethoxymethyl;

R₇ is 1–3 groups independently selected from the group consisting oflower alkyl, lower alkoxy, —COOH, NO₂, —N(R₈)(R₉), OH, and halogeno;

R₈ and R₉ are independently selected from H or lower alkyl;

R₁₀ is selected from lower alkyl, phenyl, R₇-phenyl, benzyl orR₇-benzyl;

R₁₁ is selected from OH, lower alkyl, phenyl, benzyl, R₇-phenyl orR₇-benzyl;

R₁₂ is selected from H, OH, alkoxy, phenoxy, benzyloxy,

—N(R₈)(R₉), lower alkyl, phenyl or R₇-phenyl;

R₁₃ is selected from —O—, —CH₂—, —NH—, —N(lower alkyl)—or —NC(O)R₁₉;

R₁₅, R₁₆ and R₁₇ are independently selected from the group consisting ofH and the groups defined for W; or R₁₅ is hydrogen and R₁₆ and R₁₇,together with adjacent carbon atoms to which they are attached, form adioxolanyl ring;

R₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and

R₂₀ and R₂₁ are independently selected from the group consisting ofphenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl,indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substitutedheteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryland cyclopropyl, wherein heteroaryl is as defined above.

One group of preferred compounds of Formula VI is that in which R₂₁ isselected from phenyl, W-substituted phenyl, indanyl, benzofuranyl,benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl,quinolyl or cyclopropyl,

wherein W is lower alkyl, lower alkoxy, OH, halogeno, —N(R₈)(R₉),—NHC(O)OR₁₀, —NHC(O)R₁₀, NO₂, —CN, —N₃, —SH, —S(O)₀₋₂—(lower alkyl),—COOR₁₉, —CON(R₈)(R₉), —COR₁₂, phenoxy, benzyloxy, —OCF₃, —CH═C(O)R₁₂ ortert-butyldimethylsilyloxy, wherein R₈, R₉, R₁₀, R₁₂ and R₁₉ are asdefined for Formula IV. When W is 2 or 3 substituents, the substituentscan be the same or different.

Another group of preferred compounds of Formula VI is that in which R₂₀is phenyl or W-substituted phenyl, wherein preferred meanings of W areas defined above for preferred definitions of R₂₁.

More preferred are compounds of Formula VI wherein R₂₀ is phenyl orW-substituted phenyl and R₂₁ is phenyl, W-substituted phenyl, indanyl,benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl,pyrimidinyl, quinolyl or cyclopropyl; W is lower alkyl, lower alkoxy,OH, halogeno, —N(R₈)(R₉), —NHC(O)OR₁₀, —NHC(O)R₁₀, NO₂, —CN, —N₃, —SH,—S(O)₀₋₂—(lower alkyl), —COOR₁₉, —CON(R₈)(R₉), —COR₁₂, phenoxy,benzyloxy, —CH═CHC(O)R₁₂, —OCF₃ or tert-butyl-dimethyl-silyloxy, whereinwhen W is 2 or 3 substituents, the substituents can be the same ordifferent, and wherein R₈, R₉, R₁₀, R₁₂ and R₁₉ are as defined inFormula VI.

Also preferred are compounds of Formula VI wherein R₁ is

Another group of preferred compounds of Formula VI is in which R₂ and R₃are each —CH₂— and the sum of u and v is 2, 3 or 4, with u=v=2 beingmore preferred.

R₄ is preferably B—(CH₂)_(q)— or B—(CH₂)_(e)—Z—(CH₂)_(r)—, wherein B, Z,q, e and r are as defined above. B is preferably

wherein R₁₆ and R₁₇ are each hydrogen and wherein R₁₅ is preferably H,OH, lower alkoxy, especially methoxy, or halogeno, especially chloro.

Preferably Z is —O—, e is 0, and r is 0.

Preferably q is 0–2.

R₂₀ is preferably phenyl or W-substituted phenyl.

Preferred W substituents for R₂₀ are lower alkoxy, especially methoxyand ethoxy, OH, and —C(O)R₁₂, wherein R₁₂ is preferably lower alkoxy.

Preferably R₂₁ is selected from phenyl, lower alkoxy-substituted phenyland F-phenyl.

Especially preferred are compounds of Formula VI wherein R₁ is

R₂ and R₃ are each —CH₂—, u=v=2, R₄ is B—(CH₂)_(q)—, wherein B is phenylor phenyl substituted by lower alkoxy or chloro, q is 0–2, R₂₀ isphenyl, OH-phenyl, lower alkoxy-substituted phenyl or loweralkoxycarbonyl-substituted phenyl, and R₂₁ is phenyl, loweralkoxy-substituted phenyl or F-phenyl.

Methods for making compounds of Formula VI are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,698,548, which is incorporated herein byreference.

In another embodiment, sterol or 5α-stanol absorption inhibitors usefulin the compositions, therapeutic combinations and methods of the presentinvention are represented by Formulas (VIIA) and (VIIB):

or a pharmaceutically acceptable salt or solvate thereof,wherein:

A is —CH═CH—, —C≡C— or —(CH₂)_(p)— wherein p is 0, 1 or 2;

B is

D is —(CH₂)_(m)C(O)— or —(CH₂)_(q)— wherein m is 1, 2, 3 or 4 and q is2, 3 or 4;

E is C₁₀ to C₂₀ alkyl or —C(O)—(C₉ to C₁₉)—alkyl, wherein the alkyl isstraight or branched, saturated or containing one or more double bonds;

R is hydrogen, C₁–C₁₅ alkyl, straight or branched, saturated orcontaining one or more double bonds, or B—(CH₂)_(r)—, wherein r is 0, 1,2, or 3;

R₁, R₂, R₃, R₁′, R₂′, and R₃′ are independently selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO₂, NH₂,OH, halogeno, lower alkylamino, dilower alkylamino, —NHC(O)OR₅, R₆O₂SNH—and —S(O)₂NH₂;

R₄ is

wherein n is 0, 1, 2 or 3;

R₅ is lower alkyl; and

R₆ is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein thesubstituents are 1–3 groups independently selected from the groupconsisting of lower alkyl, lower alkoxy, carboxy, NO₂, NH₂, OH,halogeno, lower alkylamino and dilower alkylamino; or a pharmaceuticallyacceptable salt thereof or a prodrug thereof.

Preferred are compounds of Formula (VIIA) wherein R is hydrogen,saturated or mono-unsaturated C₁–C₁₀ alkyl or phenyl. Another group ofpreferred compounds of Formula (VIIA) is that in which D is propyl(i.e., —(CH₂)_(q)— and q is 3). A third group of preferred compounds ofFormula (VIIA) is that wherein R₄ is p-methoxyphenyl or2,4,6-trimethoxyphenyl. Still another group of preferred compounds ofFormula (VIIA) is that wherein A is ethylene or a bond (i.e.,—(CH₂)_(p)— wherein p is zero). R₁′, R₂′, and R₃′ are preferably eachhydrogen, and preferably R₁ is hydrogen, hydroxy, nitro, lower alkoxy,amino or t-butoxycarbonyl-amino and R₂ and R₃ are each hydrogen.

More preferred are compounds of Formula (VIIA) wherein R₁′, R₂′, and R₃′are each hydrogen; R₁ is hydrogen, hydroxy, nitro, lower alkoxy, aminoor t-butoxycarbonyl-amino and R₂ and R₃ are each hydrogen; R ishydrogen, ethyl or phenyl; D is propyl; R₄ is p-methoxyphenyl or2,4,6-trimethoxyphenyl; and A is ethylene or a bond.

Preferred compounds of Formula (VIIA), wherein B′ is phenyl, are shownin the following table:

D R A B R₄ —(CH₂)₃— H — p-MeO- p-MeO-phenyl phenyl —CH₂C(O)— phenyl —phenyl p-MeO-phenyl —(CH₂)₃— H — phenyl p-MeO-phenyl —(CH₂)₃— H — p-OH-p-MeO-phenyl phenyl —(CH₂)₃— H ethylene p-MeO- p-MeO-phenyl phenyl—(CH₂)₃— H — 3-MeO- p-MeO-phenyl phenyl —(CH₂)₃— ethyl — phenylp-MeO-phenyl —(CH₂)₃— phenyl — phenyl p-MeO-phenyl —(CH₂)₃— ethyl —phenyl 2,4,6-tri-MeO- phenyl —(CH₂)₃— methyl — phenyl p-MeO-phenyl—(CH₂)₃— H — p-NH₂- p-MeO-phenyl phenyl

The first-listed compound in the above table having the (3R,4S) absolutestereochemistry is more preferred.

Preferred compounds of Formula (VIIB) are those wherein R is hydrogen,methyl, ethyl, phenyl or phenylpropyl. Another group of preferredcompounds of Formula (VIIB) is that wherein R₄ is p-methoxyphenyl or2,4,6-trimethoxyphenyl. Still another group of preferred compounds ofFormula (VIIB) is that wherein A is ethylene or a bond. Yet anothergroup of preferred compounds of Formula (VIIB) is that wherein E isdecyl, oleoyl or 7-Z-hexadecenyl. Preferably R₁, R₂ and R₃ are eachhydrogen.

More preferred compounds of Formula (VIIB) are those wherein R ishydrogen, methyl, ethyl, phenyl or phenylpropyl; R₄ is p-methoxyphenylor 2,4,6-trimethoxyphenyl; A is ethylene or a bond; E is decyl, oleoylor 7-Z-hexadecenyl; and R₁, R₂ and R₃ are each hydrogen.

A preferred compound of Formula (VIIB) is that wherein E is decyl, R ishydrogen, B-A is phenyl and R₄ is p-methoxyphenyl.

In another embodiment, sterol or 5α-stanol absorption inhibitors usefulin the compositions and methods of the present invention are representedby Formula (VIII):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (VIII) above,

R²⁶ is H or OG¹;

G and G¹ are independently selected from the group consisting of

provided that when R²⁶ is H or OH, G is not H;

R, R^(a) and R^(b) are independently selected from the group consistingof H, —OH, halogeno, —NH₂, azido, (C₁–C₆)alkoxy(C₁–C₆)—alkoxy or —W—R³⁰;

W is independently selected from the group consisting of —NH—C(O)—,—O—C(O)—, —O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—;

R² and R⁶ are independently selected from the group consisting of H,(C₁–C₆)alkyl, aryl and aryl(C₁–C₆)alkyl;

R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) are independently selected from thegroup consisting of H, (C₁–C₆)alkyl, aryl(C₁–C₆)alkyl, —C(O)(C₁–C₆)alkyland —C(O)aryl;

R³⁰ is selected from the group consisting of R³²—substituted T,R³²—substituted—T—(C₁–C₆)alkyl, R³²—substituted—(C₂–C₄)alkenyl,R³²—substituted—(C₁–C₆)alkyl, R³²—substituted—(C₃–C₇)cycloalkyl andR³²—substituted—(C₃–C₇)cycloalkyl(C₁–C₆)alkyl;

R³¹ is selected from the group consisting of H and (C₁–C₄)alkyl;

T is selected from the group consisting of phenyl, furyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl,thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is independently selected from 1–3 substituents independentlyselected from the group consisting of halogeno, (C₁–C₄)alkyl, —OH,phenoxy, —CF₃, —NO₂, (C₁–C₄)alkoxy, methylenedioxy, oxo,(C₁–C₄)alkylsulfanyl, (C₁–C₄)alkylsulfinyl, (C₁–C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁–C₄)alkyl, —C(O)—N((C₁–C₄)alkyl)₂,—C(O)—(C₁–C₄)alkyl, —C(O)—(C₁–C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁–C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

Ar¹ is aryl or R¹⁰-substituted aryl;

Ar² is aryl or R¹¹-substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone,forms the spiro group

R¹ is selected from the group consisting of

-   -   —(CH₂)_(q)—, wherein q is 2–6, provided that when Q forms a        spiro ring, q can also be zero or 1;    -   —(CH₂)_(e)—E—(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene,        —NR²²— or —S(O)₀₋₂—, e is 0–5 and r is 0–5, provided that the        sum of e and r is 1–6;    -   —(C₂–C₆)alkenylene—; and    -   —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃–C₆ cycloalkylene, f is        1–5 and g is 0–5, provided that the sum of f and g is 1–6;

R¹² is

R¹³ and R¹⁴ are independently selected from the group consisting of

—CH₂—, —CH(C₁–C₆ alkyl)—, —C(di-(C₁–C₆)alkyl), —CH═CH— and —C(C₁–C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁–C₆ alkyl)—group;

a and b are independently 0, 1, 2 or 3, provided both are not zero;

provided that when R¹³ is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, a is 1;

provided that when R¹⁴ is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, b is 1;

provided that when a is 2 or 3, the R¹³'s can be the same or different;and

provided that when b is 2 or 3, the R¹⁴'s can be the same or different;

and when Q is a bond, R¹ also can be:

X, Y and Z are independently selected from the group consisting of—CH₂—, —CH(C₁–C₆)alkyl— and —C(di-(C₁–C₆)alkyl);

R¹⁰ and R¹¹ are independently selected from the group consisting of 1–3substituents independently selected from the group consisting of(C₁–C₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹, —O(CH₂)₁₋₅OR¹⁹,—O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹, —NR¹⁹(CO)NR²⁰R²⁵,—NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰, S(O)₀₋₂R²¹,—O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁–C₆ alkylene)—COOR¹⁹,—CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halogen;

R¹⁵ and R¹⁷ are independently selected from the group consisting of—OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹ and —O(CO)NR¹⁹R²⁰;

R¹⁶ and R¹⁸ are independently selected from the group consisting of H,(C₁–C₆)alkyl and aryl; or R¹⁵ and R¹⁶ together are ═O, or R¹⁷ and R¹⁸together are ═O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1; t is 0 or 1; m, n and p are independently 0–4;

provided that at least one of s and t is 1, and the sum of m, n, p, sand t is 1–6;

provided that when p is 0 and t is 1, the sum of m, s and n is 1–5; andprovided that when p is 0 and s is 1, the sum of m, t and n is 1–5;

v is 0 or 1;

j and k are independently 1–5, provided that the sum of j, k and v is1–5;

and when Q is a bond and R¹ is

Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R¹⁹ and R²⁰ are independently selected from the group consisting of H,(C₁–C₆)alkyl, aryl and aryl-substituted (C₁–C₆)alkyl;

R²¹ is (C₁–C₆)alkyl, aryl or R²⁴-substituted aryl;

R²² is H, (C₁–C₆)alkyl, aryl (C₁–C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹;

R²³ and R²⁴ are independently 1–3 groups independently selected from thegroup consisting of H, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, —COOH, NO₂,—NR¹⁹R²⁰, —OH and halogeno; and

R²⁵ is H, —OH or (C₁–C₆)alkoxy.

Ar² is preferably phenyl or R¹¹-phenyl, especially (4-R¹¹)—substitutedphenyl. Preferred definitions of R¹¹ are lower alkoxy, especiallymethoxy, and halogeno, especially fluoro.

Ar¹ is preferably phenyl or R¹⁰-substituted phenyl, especially(4-R¹⁰)—substituted phenyl. Preferably R¹⁰ is halogeno, and morepreferably fluoro.

There are several preferred definitions for the —R¹—Q—combination ofvariables:

Q is a bond and R¹ is lower alkylene, preferably propylene;

Q is a spiro group as defined above, wherein preferably R¹³ and R¹⁴ areeach ethylene and R¹² is

and R¹ is —(CH₂)_(q) wherein q is 0–6;

Q is a bond and R¹ is

wherein the variables are chosen such that R¹ is —O—CH₂—CH(OH)—;

Q is a bond and R¹

wherein the is variables are chosen such that R¹ is —CH(OH)—(CH₂)₂—; and

Q is a bond and R¹ is

wherein the variables are chosen such that R¹ is —CH(OH)—CH₂—S(O)₀₋₂—.

A preferred compound of Formula (VIII) therefore, is one wherein G andG¹ are as defined above and in which the remaining variables have thefollowing definitions:

Ar¹ is phenyl or R¹⁰-substituted phenyl, wherein R¹⁰ is halogeno;

Ar² is phenyl or R¹¹-phenyl, wherein R¹¹ is 1 to 3 substituentsindependently selected from the group consisting of C₁–C₆ alkoxy andhalogeno;

Q is a bond and R¹ is lower alkylene; Q, with the 3-position ring carbonof the azetidinone, forms the group

wherein preferably R¹³ and R¹⁴ are each ethylene and a and b are each 1,and wherein R¹² is

Q is a bond and R¹ is —O—CH₂—CH(OH)—; Q is a bond and R¹ is—CH(OH)—(CH₂)₂—; or Q is a bond and R¹ is —CH(OH)—CH₂—S(O)₀₋₂—.

Preferred variables for G and G¹ groups of the formulae

are as follows:

R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from the groupconsisting of H, (C₁–C₆)alkyl, benzyl and acetyl.

Preferred variables for group G or G¹ of the formula:

are as follows:

R³, R^(3a), R⁴ and R^(4a) are selected from the group consisting of H,(C₁–C₆)alkyl, benzyl and acetyl;

R, R^(a) and R^(b) are independently selected from the group consistingof H, —OH, halogeno, —NH₂, azido, (C₁–C₆)alkoxy(C₁–C₆)alkoxy and —W—R³⁰,

wherein W is —O—C(O)— or —O—C(O)—NR³¹—, R³¹ is H and R³⁰ is(C₁–C₆)alkyl, —C(O)—(C₁–C₄)alkoxy—(C₁–C₆)alkyl, T, T—(C₁–C₆)alkyl, or T,T—(C₁–C₆)alkyl wherein T is substituted by one or two halogeno or(C₁–C₆)alkyl groups.

Preferred R³⁰ substituents are selected from the group consisting of:2-fluorophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyl, 2-methylphenyl,2-thienylmethyl, 2-methoxy-carbonylethyl, thiazol-2-yl-methyl, 2-furyl,2-methoxycarbonylbutyl and phenyl.

Preferred combinations of R, R^(a) and R^(b) are as follows:

-   -   1) R, R^(a) and R^(b) are independently —OH or —O—C(O)—NH—R³⁰,        especially wherein R^(a) is —OH and R and R^(b) are        —O—C(O)—NH—R³⁰ and R³⁰ is selected from the preferred        substituents identified above, or wherein R and R^(a) are each        —OH and R^(b) is —O—C(O)—NH—R³⁰ wherein R³⁰ is 2-fluorophenyl,        2,4-difluoro-phenyl, 2,6-dichlorophenyl;    -   2) R^(a) is —OH, halogeno, azido or (C₁–C₆)—alkoxy(C₁–C₆)alkoxy,        R^(b) is H, halogeno, azido or (C₁–C₆)alkoxy(C₁–C₆)—alkoxy, and        R is —O—C(O)—NH—R³⁰, especially compounds wherein R^(a) is —OH,        R^(b) is H and R³⁰ is 2-fluorophenyl;    -   3) R, R^(a) and R^(b) are independently —OH or —O—C(O)—R³⁰ and        R³⁰ is (C₁–C₆)alkyl, T, or T substituted by one or two halogeno        or (C₁–C₆)alkyl groups, especially compounds wherein R is —OH        and R^(a) and R^(b) are —O—C(O)—R³⁰ wherein R³⁰ is 2-furyl; and    -   4) R, R^(a) and R^(b) are independently —OH or halogeno. Three        additional classes of preferred compounds are those wherein the        C¹′ anomeric oxy is beta, wherein the C²′ anomeric oxy is beta,        and wherein the R group is alpha. G and G¹ are preferably        selected from:

wherein Ac is acetyl and Ph is phenyl.

Preferably, R²⁶ is H or OH, more preferably H. The —O—G substituent ispreferably in the 4-position of the phenyl ring to which it is attached.

In another embodiment, sterol and/or 5α-stanol absorption inhibitorsuseful in the compositions and methods of the present invention arerepresented by Formula (IX) below:

or a pharmaceutically acceptable salt or solvate thereof, wherein inFormula (IX):

R¹ is selected from the group consisting of H, G, G¹, G², —SO₃H and—PO₃H;

G is selected from the group consisting of: H,

(Sugar Derivatives)

wherein R, R^(a) and R^(b) are each independently selected from thegroup consisting of H, —OH, halo, —NH₂, azido,(C₁–C₆)alkoxy(C₁–C₆)alkoxy or —W—R³⁰;

W is independently selected from the group consisting of —NH—C(O)—,—O—C(O)—, —O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—;

R² and R⁶ are each independently selected from the group consisting ofH, (C₁–C₆)alkyl, acetyl, aryl and aryl(C₁–C₆)alkyl;

R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) are each independently selected fromthe group consisting of H, (C₁–C₆)alkyl, acetyl, aryl(C₁–C₆)alkyl,—C(O)(C₁–C₆)alkyl and —C(O)aryl;

R³⁰ is independently selected from the group consisting ofR³²-substituted T, R³²-substituted-T—(C₁–C₆)alkyl,R³²-substituted—(C₂–C₄)alkenyl, R³²-substituted—(C₁–C₆)alkyl,R³²-substituted—(C₃–C₇)cycloalkyl andR³²-substituted—(C₃–C₇)cycloalkyl(C₁–C₆)alkyl;

R³¹ is independently selected from the group consisting of H and(C₁–C₄)alkyl;

T is independently selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is independently selected from 1–3 substituents which are eachindependently selected from the group consisting of H, halo,(C₁–C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁–C₄)alkoxy, methylenedioxy,oxo, (C₁–C₄)alkylsulfanyl, (C₁–C₄)alkylsulfinyl, (C₁–C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁–C₄)alkyl, —C(O)—N((C₁–C₄)alkyl)₂,—C(O)—(C₁–C₄)alkyl, —C(O)—(C₁–C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁–C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

G¹ is represented by the structure:

wherein R³³ is independently selected from the group consisting ofunsubstituted alkyl, R³⁴—substituted alkyl, (R³⁵)(R³⁶)alkyl—,

R³⁴ is one to three substituents, each R³⁴ being independently selectedfrom the group consisting of HOOC—, HS—, (CH₃)S—, H₂N—, (NH₂)(NH)C(NH)—,(NH₂)C(O)— and HOOCCH(NH₃ ⁺)CH₂SS—;

R³⁵ is independently selected from the group consisting of H and NH₂—;

R³⁶ is independently selected from the group consisting of H,unsubstituted alkyl, R³⁴-substituted alkyl, unsubstituted cycloalkyl andR³⁴-substituted cycloalkyl;

G² is represented by the structure:

wherein R³⁷ and R³⁸ are each independently selected from the groupconsisting of (C₁–C₆)alkyl and aryl;

R²⁶ is one to five substituents, each R²⁶ being independently selectedfrom the group consisting of:

a) H;

b) —OH;

c) —OCH₃;

d) fluorine;

e) chlorine;

f) —O—G;

g) —O—G¹;

h) —O—G²;

i) —SO₃H; and

j) —PO₃H;

provided that when R¹ is H, R²⁶ is not H, —OH, —OCH₃ or —O—G;

Ar¹ is aryl, R¹⁰-substituted aryl, heteroaryl or R¹⁰-substitutedheteroaryl;

Ar² is aryl, R¹¹-substituted aryl, heteroaryl or R¹¹-substitutedheteroaryl;

L is selected from the group consisting of:

-   -   a) a covalent bond;    -   b) —(CH₂)_(q)—, wherein q is 1–6;    -   c) —(CH₂)_(e)—E—(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene,        —NR²²— or —S(O)₀₋₂—, e is 0–5 and r is 0–5, provided that the        sum of e and r is 1–6;    -   d) —(C₂–C₆)alkenylene—;    -   e) —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃–C₆cycloalkylene, f        is 1–5 and g is 0–5, provided that the sum of f and g is 1–6;        and    -   f)

wherein M is —O—, —S—, —S(O)— or —S(O)₂—;

X, Y and Z are each independently selected from the group consisting of—CH₂—, —CH(C₁–C₆)alkyl— and —C(di-(C₁–C₆)alkyl)—;

R⁸ is selected from the group consisting of H and alkyl;

R¹⁰ and R¹¹ are each independently selected from the group consisting of1–3 substituents which are each independently selected from the groupconsisting of (C₁–C₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹,—O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹,—NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰,S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁–C₆alkylene)—COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halo;

R¹⁵ and R¹⁷ are each independently selected from the group consisting of—OR¹⁹, —OC(O)R¹⁹, —OC(O)OR²¹, —OC(O)NR¹⁹R²⁰;

R¹⁶ and R¹⁸are each independently selected from the group consisting ofH, (C₁–C₆)alkyl and aryl;

or R¹⁵ and R¹⁶ together are ═O, or R¹⁷ and R¹⁸ together are ═O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1;

t is 0 or 1;

m, n and p are each independently selected from 0–4;

provided that at least one of s and t is 1, and the sum of m, n, p, sand t is 1–6; provided that when p is 0 and t is 1, the sum of m, n andp is 1–5; and provided that when p is 0 and s is 1, the sum of m, t andn is 1–5;

v is 0 or 1;

j and k are each independently 1–5, provided that the sum of j, k and vis 1–5;

Q is a bond, —(CH₂)_(q)—, wherein q is 1–6, or, with the 3-position ringcarbon of the azetidinone, forms the spiro group

wherein R¹² is

R¹³ and R¹⁴ are each independently selected from the group consisting of—CH₂—, —CH(C₁–C₆ alkyl)—, —C(di-(C₁–C₆) alkyl), —CH═CH— and —C(C₁–C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁–C₆ alkyl)—group;

a and b are each independently 0, 1, 2 or 3, provided both are not zero;provided that when R¹³ is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, a is 1;provided that when R¹⁴ is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, b is 1;provided that when a is 2 or 3, the R¹³'s can be the same or different;and provided that when b is 2 or 3, the R¹⁴'s can be the same ordifferent;

and when Q is a bond and L is

then Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R¹⁹ and R²⁰ are each independently selected from the group consisting ofH, (C₁–C₆)alkyl, aryl and aryl-substituted (C₁–C₆)alkyl;

R²¹ is (C₁–C₆)alkyl, aryl or R²⁴-substituted aryl;

R²² is H, (C₁–C₆)alkyl, aryl (C₁–C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹;

R²³ and R²⁴ are each independently selected from the group consisting of1–3 substituents which are each independently selected from the groupconsisting of H, (C₁–C₆)alkyl, (C₁–C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OHand halo; and

R²⁵ is H, —OH or (C₁–C₆)alkoxy.

Examples of compounds of Formula (IX) which are useful in the methodsand combinations of the present invention and methods for making suchcompounds are disclosed in U.S. patent application Ser. No. 10/166,942,filed Jun. 11, 2002, incorporated herein by reference. An example of auseful compound of this invention is one represented by the formula X:

wherein R¹ is defined as above.

A more preferred compound is one represented by formula XI:

Another useful compound is represented by Formula XII:

In another embodiment, compositions, pharmaceutical compositions,therapeutic combinations, kits and methods of treatment as describedabove are provided which comprise: (a) at least one obesity controlmedication; and (b) at least one sterol absorption inhibitor orpharmaceutically acceptable salts thereof or prodrugs thereof. Suitablesterol absorption inhibitors include substituted azetidinone compoundsor substituted β-lactam compounds such as compounds discussed above inFormulae I–XII. Other useful substituted azetidinone compounds includeN-sulfonyl-2-azetidinones such as are disclosed in U.S. Pat. No.4,983,597 and ethyl 4—(2-oxoazetidin-4-yl)phenoxy-alkanoates such as aredisclosed in Ram et al., Indian J. Chem. Sect. B. 29B, 12 (1990), p.1134–7, which are incorporated by reference herein.

The compounds of Formulae I–XII can be prepared by known methods,including the methods discussed above and, for example, WO 93/02048describes the preparation of compounds wherein —R¹—Q—is alkylene,alkenylene or alkylene interrupted by a hetero atom, phenylene orcycloalkylene; WO 94/17038 describes the preparation of compoundswherein Q is a spirocyclic group; WO 95/08532 describes the preparationof compounds wherein —R¹—Q—is a hydroxy-substituted alkylene group;PCT/US95/03196 describes compounds wherein —R¹—Q—is ahydroxy-substituted alkylene attached to the Ar¹ moiety through an —O—or S(O)₀₋₂— group; and U.S. Ser. No. 08/463,619, filed Jun. 5, 1995, nowU.S. Pat. No. 5,633,246, describes the preparation of compounds wherein—R¹—Q—is a hydroxy-substituted alkylene group attached the azetidinonering by a —S(O)₀₋₂— group.

The daily dose of the sterol absorption inhibitor(s) administered to thesubject can range from about 0.1 to about 1000 mg per day, preferablyabout 0.25 to about 50 mg/day, and more preferably about 10 mg per day,given in a single dose or 2–4 divided doses. The exact dose, however, isdetermined by the attending clinician and is dependent on the potency ofthe compound administered, the age, weight, condition and response ofthe patient.

For administration of pharmaceutically acceptable salts of the abovecompounds, the weights indicated above refer to the weight of the acidequivalent or the base equivalent of the therapeutic compound derivedfrom the salt.

The compositions or therapeutic combinations of the present inventioncan further comprise at least one (one or more) activators forperoxisome proliferator-activated receptors (PPAR) which are chemicallydifferent from the obesity control medications above. These activatorsact as agonists for the peroxisome proliferator-activated receptors.Three subtypes of PPAR have been identified, and these are designated asperoxisome proliferator-activated receptor alpha (PPARα), peroxisomeproliferator-activated receptor gamma (PPARγ) and peroxisomeproliferator-activated receptor delta (PPARδ). It should be noted thatPPARδ is also referred to in the literature as PPARβ and as NUC1, andeach of these names refers to the same receptor.

PPARα regulates the metabolism of lipids. PPARα is activated by fibratesand a number of medium and long-chain fatty acids, and it is involved instimulating β-oxidation of fatty acids. The PPARγ receptor subtypes areinvolved in activating the program of adipocyte differentiation and arenot involved in stimulating peroxisome proliferation in the liver. PPARδhas been identified as being useful in increasing high densitylipoprotein (HDL) levels in humans. See, e.g., WO 97/28149.

PPARα activator compounds are useful for, among other things, loweringtriglycerides, moderately lowering LDL levels and increasing HDL levels.Useful examples of PPARα activators include fibrates.

Non-limiting examples of suitable fibric acid derivatives (“fibrates”)include clofibrate (such as ethyl2—(p-chlorophenoxy)—2-methyl-propionate, for example ATROMID-S® Capsuleswhich are commercially available from Wyeth-Ayerst); gemfibrozil (suchas 5—(2,5-dimethylphenoxy)—2,2-dimethylpentanoic acid, for exampleLOPID® tablets which are commercially available from Parke Davis);ciprofibrate (C.A.S. Registry No. 52214-84-3, see U.S. Pat. No.3,948,973 which is incorporated herein by reference); bezafibrate(C.A.S. Registry No. 41859-67-0, see U.S. Pat. No. 3,781,328 which isincorporated herein by reference); clinofibrate (C.A.S. Registry No.30299-08-2, see U.S. Pat. No. 3,716,583 which is incorporated herein byreference); binifibrate (C.A.S. Registry No. 69047-39-8, see BE 884722which is incorporated herein by reference); lifibrol (C.A.S. RegistryNo. 96609-16-4); fenofibrate (such as TRICOR® micronized fenofibrate(2-[4—(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethylester) which is commercially available from Abbott Laboratories orLIPANTHYL® micronized fenofibrate which is commercially available fromLabortoire Founier, France) and mixtures thereof. These compounds can beused in a variety of forms, including but not limited to acid form, saltform, racemates, enantiomers, zwitterions and tautomers.

Other examples of PPARα activators useful with the practice of thepresent invention include suitable fluorophenyl compounds as disclosedin U.S. Pat. No. 6,028,109 which is incorporated herein by reference;certain substituted phenylpropionic compounds as disclosed in WO00/75103 which is incorporated herein by reference; and PPARα activatorcompounds as disclosed in WO 98/43081 which is incorporated herein byreference.

Non-limiting examples of PPARγ activator include suitable derivatives ofglitazones or thiazolidinediones, such as, troglitazone (such asREZULIN® troglitazone(-5-[[4-[3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione)commercially available from Parke-Davis); rosiglitazone (such asAVANDIA® rosiglitazone maleate(-5-[[4-[2—(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione,-2-butenedioate) commercially available from SmithKline Beecham) andpioglitazone (such as ACTOS™ pioglitazone hydrochloride(5-[[4-[2—(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-]thiazolidinedionemonohydrochloride) commercially available from Takeda Pharmaceuticals).Other useful thiazolidinediones include ciglitazone, englitazone,darglitazone and BRL 49653 as disclosed in WO 98/05331 which isincorporated herein by reference; PPARγ activator compounds disclosed inWO 00/76488 which is incorporated herein by reference; and PPARγactivator compounds disclosed in U.S. Pat. No. 5,994,554 which isincorporated herein by reference.

Other useful classes of PPARγ activator compounds include certainacetylphenols as disclosed in U.S. Pat. No. 5,859,051 which isincorporated herein by reference; certain quinoline phenyl compounds asdisclosed in WO 99/20275 which is incorporated herein by reference; arylcompounds as disclosed by WO 99/38845 which is incorporated herein byreference; certain 1,4-disubstituted phenyl compounds as disclosed in WO00/63161; certain aryl compounds as disclosed in WO 01/00579 which isincorporated herein by reference; benzoic acid compounds as disclosed inWO 01/12612 & WO 01/12187 which are incorporated herein by reference;and substituted 4-hydroxy-phenylalconic acid compounds as disclosed inWO 97/31907 which is incorporated herein by reference.

PPARδ compounds are useful for, among other things, loweringtriglyceride levels or raising HDL levels. Non-limiting examples ofPPARδ activators include suitable thiazole and oxazole derivates, suchas C.A.S. Registry No. 317318-32-4, as disclosed in WO 01/00603 which isincorporated herein by reference); certain fluoro, chloro orthio phenoxyphenylacetic acids as disclosed in WO 97/28149 which is incorporatedherein by reference; suitable non-β-oxidizable fatty acid analogues asdisclosed in U.S. Pat. No. 5,093,365 which is incorporated herein byreference; and PPARδ compounds as disclosed in WO 99/04815 which isincorporated herein by reference.

Moreover, compounds that have multiple functionality for activatingvarious combinations of PPARα, PPARγ and PPARδ are also useful with thepractice of the present invention. Non-limiting examples include certainsubstituted aryl compounds as disclosed in U.S. Pat. No. 6,248,781; WO00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; and WO00/63153, all of which are incorporated herein by reference, aredescribed as being useful PPARα and/or PPARγ activator compounds. Othernon-limiting examples of useful PPARα and/or PPARγ activator compoundsinclude activator compounds as disclosed in WO 97/25042 which isincorporated herein by reference; activator compounds as disclosed in WO00/63190 which is incorporated herein by reference; activator compoundsas disclosed in WO 01/21181 which is incorporated herein by reference;biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120 which isincorporated herein by reference; compounds as disclosed in WO 00/63196and WO 00/63209 which are incorporated herein by reference; substituted5-aryl-2,4-thiazolidinediones compounds as disclosed in U.S. Pat. No.6,008,237 which is incorporated herein by reference;arylthiazolidinedione and aryloxazolidinedione compounds as disclosed inWO 00/78312 and WO 00/78313G which are incorporated herein by reference;GW2331 or(2—(4-[difluorophenyl]-1heptylureido)ethyl]phenoxy)—2-methylbutyriccompounds as disclosed in WO 98/05331 which is incorporated herein byreference; aryl compounds as disclosed in U.S. Pat. No. 6,166,049 whichis incorporated herein by reference; oxazole compounds as disclosed inWO 01/17994 which is incorporated herein by reference; and dithiolanecompounds as disclosed in WO 01/25225 and WO 01/25226 which areincorporated herein by reference.

Other useful PPAR activator compounds include substitutedbenzylthiazolidine-2,4-dione compounds as disclosed in WO 01/14349, WO01/14350 and WO/01/04351 which are incorporated herein by reference;mercaptocarboxylic compounds as disclosed in WO 00/50392 which isincorporated herein by reference; ascofuranone compounds as disclosed inWO 00/53563 which is incorporated herein by reference; carboxyliccompounds as disclosed in WO 99/46232 which is incorporated herein byreference; compounds as disclosed in WO 99/12534 which is incorporatedherein by reference; benzene compounds as disclosed in WO 99/15520 whichis incorporated herein by reference; o-anisamide compounds as disclosedin WO 01/21578 which is incorporated herein by reference; and PPARactivator compounds as disclosed in WO 01/40192 which is incorporatedherein by reference.

The peroxisome proliferator-activated receptor(s) activator(s) areadministered in a therapeutically effective amount to treat thespecified condition, for example in a daily dose preferably ranging fromabout 50 to about 3000 mg per day, and more preferably about 50 to about2000 mg per day, given in a single dose or 2–4 divided doses. The exactdose, however, is determined by the attending clinician and is dependenton such factors as the potency of the compound administered, the age,weight, condition and response of the patient.

Also useful with the present invention are compositions or therapeuticcombinations that can further comprise one or more pharmacological ortherapeutic agents or drugs such as cholesterol biosynthesis inhibitorsand/or lipid-lowering agents discussed below.

Non-limiting examples of cholesterol biosynthesis inhibitors for use inthe compositions, therapeutic combinations and methods of the presentinvention include competitive inhibitors of HMG CoA reductase, therate-limiting step in cholesterol biosynthesis, squalene synthaseinhibitors, squalene epoxidase inhibitors and mixtures thereof.Non-limiting examples of suitable HMG CoA reductase inhibitors includestatins such as lovastatin (for example MEVACOR® which is available fromMerck & Co.), pravastatin (for example PRAVACHOL® which is availablefrom Bristol Meyers Squibb), fluvastatin, simvastatin (for exampleZOCOR® which is available from Merck & Co.), atorvastatin, cerivastatin,CI-981, rivastatin (sodium7—(4-fluorophenyl)—2,6-diisopropyl-5-methoxymethylpyridin-3-yl)—3,5-dihydroxy-6-heptanoate)and pitavastatin (such as NK-104 of Negma Kowa of Japan); HMG CoAsynthetase inhibitors, for example L-659,699((E,E)—11-[3′R—(hydroxy-methyl)—4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid); squalene synthesis inhibitors, for example squalestatin 1; andsqualene epoxidase inhibitors, for example, NB-598((E)—N-ethyl-N—(6,6-dimethyl-2-hepten-4-ynyl)—3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride) and other sterol biosynthesis inhibitors such as DMP-565.Preferred HMG CoA reductase inhibitors include lovastatin, pravastatinand simvastatin. The most preferred HMG CoA reductase inhibitor issimvastatin.

Generally, a total daily dosage of cholesterol biosynthesis inhibitor(s)can range from about 0.1 to about 160 mg per day, and preferably about0.2 to about 80 mg/day in single or 2–3 divided doses.

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more bile acid sequestrants. Bileacid sequestrants bind bile acids in the intestine, interrupting theenterohepatic circulation of bile acids and causing an increase in thefaecal excretion of steroids. Use of bile acid sequestrants is desirablebecause of their non-systemic mode of action. Bile acid sequestrants canlower intrahepatic cholesterol and promote the synthesis of apo B/E(LDL) receptors which bind LDL from plasma to further reduce cholesterollevels in the blood.

Non-limiting examples of suitable bile acid sequestrants includecholestyramine (a styrene-divinylbenzene copolymer containing quaternaryammonium cationic groups capable of binding bile acids, such asQUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available fromBristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are availablefrom Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)—trimethylammoniumbromide) which are available from Sankyo), water soluble derivativessuch as 3,3-ioene, N—(cycloalkyl) alkylamines and poliglusam, insolublequaternized polystyrenes, saponins and mixtures thereof. Other usefulbile acid sequestrants are disclosed in PCT Patent Applications Nos. WO97/11345 and WO 98/57652, and U.S. Pat. Nos. 3,692,895 and 5,703,188which are incorporated herein by reference. Suitable inorganiccholesterol sequestrants include bismuth salicylate plus montmorilloniteclay, aluminum hydroxide and calcium carbonate antacids.

Generally, a total daily dosage of bile acid sequestrant(s) can rangefrom about 1 to about 50 grams per day, and preferably about 2 to about16 grams per day in single or 2–4 divided doses.

The compositions or treatments of the present invention can furthercomprise one or more ileal bile acid transport (“IBAT”) inhibitors (orapical sodium co-dependent bile acid transport (“ASBT”) inhibitors)coadministered with or in combination with the peroxisomeproliferator-activated receptor activator(s) and sterol absorptioninhibitor(s) discussed above. The IBAT inhibitors can inhibit bile acidtransport to reduce LDL cholesterol levels. Non-limiting examples ofsuitable IBAT inhibitors include benzothiepines such as therapeuticcompounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxidestructure such as are disclosed in PCT Patent Application WO 00/38727which is incorporated herein by reference.

Generally, a total daily dosage of IBAT inhibitor(s) can range fromabout 0.01 to about 1000 mg/day, and preferably about 0.1 to about 50mg/day in single or 2–4 divided doses.

The compositions or treatments of the present invention can furthercomprise nicotinic acid (niacin) and/or derivatives thereof. As usedherein, “nicotinic acid derivative” means a compound comprising apyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure,including acid forms, salts, esters, zwitterions and tautomers, whereavailable. Examples of nicotinic acid derivatives include niceritrol,nicofuranose and acipimox (5-methyl pyrazine-2-carboxylic acid 4-oxide).Nicotinic acid and its derivatives inhibit hepatic production of VLDLand its metabolite LDL and increases HDL and apo A-1 levels. An exampleof a suitable nicotinic acid product is NIASPAN® (niacinextended-release tablets) which are available from Kos.

Generally, a total daily dosage of nicotinic acid or a derivativethereof can range from about 500 to about 10,000 mg/day, preferablyabout 1000 to about 8000 mg/day, and more preferably about 3000 to about6000 mg/day in single or divided doses.

The compositions or treatments of the present invention can furthercomprise one or more AcylCoA:Cholesterol O-acyltransferase (“ACAT”)Inhibitors, which can reduce LDL and VLDL levels, coadministered with orin combination with the peroxisome proliferator-activated receptoractivator(s) and sterol absorption inhibitor(s) discussed above. ACAT isan enzyme responsible for esterifying excess intracellular cholesteroland may reduce the synthesis of VLDL, which is a product of cholesterolesterification, and overproduction of apo B-100-containing lipoproteins.

Non-limiting examples of useful ACAT inhibitors include avasimibe([[2,4,6-tris(1-methylethyl )phenyl]acetyl]sulfamic acid,2,6-bis(1-methylethyl)phenyl ester, formerly known as CI-1011), HL-004,lecimibide (DuP-128) and CL-277082(N—(2,4-difluorophenyl)—N-[[4—(2,2-dimethylpropyl)phenyl]methyl]-N-heptylurea).See P. Chang et al., “Current, New and Future Treatments inDyslipidaemia and Atherosclerosis”, Drugs 2000 July;60(1); 55–93, whichis incorporated by reference herein.

Generally, a total daily dosage of ACAT inhibitor(s) can range fromabout 0.1 to about 1000 mg/day in single or 2–4 divided doses.

The compositions or treatments of the present invention can furthercomprise one or more Cholesteryl Ester Transfer Protein (“CETP”)Inhibitors coadministered with or in combination with the peroxisomeproliferator-activated receptor activator(s) and sterol absorptioninhibitor(s) discussed above. CETP is responsible for the exchange ortransfer of cholesteryl ester carrying HDL and triglycerides in VLDL.

Non-limiting examples of suitable CETP inhibitors are disclosed in PCTPatent Application No. WO 00/38721 and U.S. Pat. No. 6,147,090, whichare incorporated herein by reference. Pancreatic cholesteryl esterhydrolase (pCEH) inhibitors such as WAY-121898 also can becoadministered with or in combination with the peroxisomeproliferator-activated receptor(s) activator and sterol absorptioninhibitor(s) discussed above.

Generally, a total daily dosage of CETP inhibitor(s) can range fromabout 0.01 to about 1000 mg/day, and preferably about 0.5 to about 20mg/kg body weight/day in single or divided doses.

The compositions or treatments of the present invention can furthercomprise probucol or derivatives thereof (such as AGI-1067 and otherderivatives disclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250), whichcan reduce LDL levels, coadministered with or in combination with theperoxisome proliferator-activated receptor activator(s) and sterolabsorption inhibitor(s) discussed above.

Generally, a total daily dosage of probucol or derivatives thereof canrange from about 10 to about 2000 mg/day, and preferably about 500 toabout 1500 mg/day in single or 2–4 divided doses.

The compositions or treatments of the present invention can furthercomprise low-density lipoprotein (LDL) receptor activators,coadministered with or in combination with the peroxisomeproliferator-activated receptor activator(s) and sterol absorptioninhibitor(s) discussed above. Non-limiting examples of suitableLDL-receptor activators include HOE-402, an imidazolidinyl-pyrimidinederivative that directly stimulates LDL receptor activity. See M.Huettinger et al., “Hypolipidemic activity of HOE-402 is Mediated byStimulation of the LDL Receptor Pathway”, Arterioscler. Thromb. 1993;13:1005–12.

Generally, a total daily dosage of LDL receptor activator(s) can rangefrom about 1 to about 1000 mg/day in single or 2–4 divided doses.

The compositions or treatments of the present invention can furthercomprise fish oil, which contains Omega 3 fatty acids (3-PUFA), whichcan reduce VLDL and triglyceride levels, coadministered with or incombination with the peroxisome proliferator-activated receptoractivator(s) and sterol absorption inhibitor(s) discussed above.Generally, a total daily dosage of fish oil or Omega 3 fatty acids canrange from about 1 to about 30 grams per day in single or 2–4 divideddoses.

The compositions or treatments of the present invention can furthercomprise natural water soluble fibers, such as psyllium, guar, oat andpectin, which can reduce cholesterol levels. Generally, a total dailydosage of natural water soluble fibers can range from about 0.1 to about10 grams per day in single or 2–4 divided doses.

The compositions or treatments of the present invention can furthercomprise plant sterols, plant stanols and/or fatty acid esters of plantstanols, such as sitostanol ester used in BENECOL® margarine, which canreduce cholesterol levels. Generally, a total daily dosage of plantsterols, plant stanols and/or fatty acid esters of plant stanols canrange from about 0.5 to about 20 grams per day in single or 2–4 divideddoses.

The compositions or treatments of the present invention can furthercomprise antioxidants, such as probucol, tocopherol, ascorbic acid,β-carotene and selenium, or vitamins such as vitamin B₆ or vitamin B₁₂.Generally, a total daily dosage of antioxidants or vitamins can rangefrom about 0.05 to about 10 grams per day in single or 2–4 divideddoses.

The compositions or treatments of the present invention can furthercomprise monocyte and macrophage inhibitors such as polyunsaturatedfatty acids (PUFA), thyroid hormones including throxine analogues suchas CGS-26214 (a thyroxine compound with a fluorinated ring), genetherapy and use of recombinant proteins such as recombinant apo E.Generally, a total daily dosage of these agents can range from about0.01 to about 1000 mg/day in single or 2–4 divided doses.

The present invention also provides a composition or therapeuticcombination comprising (a) at least one AcylCoA:CholesterolO-acyltransferase Inhibitor and (b) at least one substituted azetidinonecompound or substituted β-lactam compound or a pharmaceuticallyacceptable salt thereof or a prodrug thereof.

Also useful with the present invention are compositions or therapeuticcombinations which further comprise hormone replacement agents andcompositions. Useful hormone agents and compositions for hormonereplacement therapy of the present invention include androgens,estrogens, progestins, their pharmaceutically acceptable salts andderivatives. Combinations of these agents and compositions are alsouseful.

The dosage of androgen and estrogen combinations vary, desirably fromabout 1 mg to about 4 mg androgen and from about 1 mg to about 3 mgestrogen. Examples include, but are not limited to, androgen andestrogen combinations such as the combination of esterified estrogens(sodium estrone sulfate and sodium equilin sulfate) andmethyltestosterone (17-hydroxy-17-methyl—, (17B)—androst-4-en-3-one)available from Solvay Pharmaceuticals, Inc., Marietta, Ga., under thetradename Estratest.

Estrogens and estrogen combinations may vary in dosage from about 0.01mg up to 8 mg, desirably from about 0.3 mg to about 3.0 mg. Examples ofuseful estrogens and estrogen combinations include:

(a) the blend of nine (9) synthetic estrogenic substances includingsodium estrone sulfate, sodium equilin sulfate, sodium17α-dihydroequilin sulfate, sodium 17α-estradiol sulfate, sodium17β-dihydroequilin sulfate, sodium 17α-dihydroequilenin sulfate, sodium17β-dihydroequilenin sulfate, sodium equilenin sulfate and sodium17β-estradiol sulfate; available from Duramed Pharmaceuticals, Inc.,Cincinnati, Ohio, under the tradename Cenestin;

(b) ethinyl estradiol(19-nor-17α-pregna-1,3,5(10)—trien-20-yne-3,17-diol; available bySchering Plough Corporation, Kenilworth, N.J., under the tradenameEstinyl;

(c) esterified estrogen combinations such as sodium estrone sulfate andsodium equilin sulfate; available from Solvay under the tradenameEstratab and from Monarch Pharmaceuticals, Bristol, Tenn., under thetradename Menest;

(d) estropipate (piperazine estra-1,3,5(10)—trien-17-one,3—(sulfooxy)—estrone sulfate); available from Pharmacia & Upjohn,Peapack, N.J., under the tradename Ogen and from Women First HealthCare, Inc., San Diego, Calif., under the tradename Ortho-Est; and

(e) conjugated estrogens (17 α-dihydroequilin, 17α-estradiol, and17β-dihydroequilin); available from Wyeth-Ayerst Pharmaceuticals,Philadelphia, Pa., under the tradename Premarin.

Progestins and estrogens may also be administered with a variety ofdosages, generally from about 0.05 to about 2.0 mg progestin and about0.001 mg to about 2 mg estrogen, desirably from about 0.1 mg to about 1mg progestin and about 0.01 mg to about 0.5 mg estrogen. Examples ofprogestin and estrogen combinations that may vary in dosage and regimeninclude:

(a) the combination of estradiol (estra-1,3,5(10)—triene-3,17β-diolhemihydrate) andnorethindrone(17β-acetoxy-19-nor-17α-pregn-4-en-20-yn-3-one); which isavailable from Pharmacia & Upjohn, Peapack, N.J., under the tradenameActivella;

(b) the combination of levonorgestrel(d(−)—13β-ethyl-17α-ethinyl-17β-hydroxygon-4-en-3-one) and ethinylestradial; available from Wyeth-Ayerst under the tradename Alesse, fromWatson Laboratories, Inc., Corona, Calif., under the tradenames Levoraand Trivora, Monarch Pharmaceuticals, under the tradename Nordette, andfrom Wyeth-Ayerst under the tradename Triphasil;

(c) the combination of ethynodiol diacetate(19-nor-17α-pregn-4-en-20-yne-3β,17-diol diacetate) and ethinylestradiol; available from G. D. Searle & Co., Chicago, Ill., under thetradename Demulen and from Watson under the tradename Zovia;

(d) the combination of desogestrel(13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol) andethinyl estradiol; available from Organon under the tradenames Desogenand Mircette, and from Ortho-McNeil Pharmaceutical, Raritan, N.J., underthe tradename Ortho-Cept;

(e) the combination of norethindrone and ethinyl estradiol; availablefrom Parke-Davis, Morris Plains, N.J., under the tradenames Estrostepand femhrt, from Watson under the tradenames Microgestin, Necon, andTri-Norinyl, from Ortho-McNeil under the tradenames Modicon andOrtho-Novum, and from Warner Chilcott Laboratories, Rockaway, N.J.,under the tradename Ovcon;

(f) the combination of norgestrel((±)—13-ethyl-17-hydroxy-18,19-dinor-17α-preg-4-en-20-yn-3-one) andethinyl estradiol; available from Wyeth-Ayerst under the tradenamesOvral and Lo/Ovral, and from Watson under the tradenames Ogestrel andLow-Ogestrel;

(g) the combination of norethindrone, ethinyl estradiol, and mestranol(3-methoxy-19-nor-17α-pregna-1,3,5(10)—trien-20-yn-17-ol); availablefrom Watson under the tradenames Brevicon and Norinyl;

(h) the combination of 17β-estradiol(estra-1,3,5(10)—triene-3,17β-diol)and micronized norgestimate(17α-17—(Acetyloxyl)—13-ethyl-18,19-dinorpregn-4-en-20-yn-3-one3-oxime);available from Ortho-McNeil under the tradename Ortho-Prefest;

(i) the combination of norgestimate(18,19-dinor-17-pregn-4-en-20-yn-3-one, 17—(acetyloxy)—13-ethyl—,oxime,(17(α)—(+)—) and ethinyl estradiol; available from Ortho-McNeil underthe tradenames Ortho Cyclen and Ortho Tri-Cyclen; and

j) the combination of conjugated estrogens (sodium estrone sulfate andsodium equilin sulfate) and medroxyprogesterone acetate(20-dione,17—(acetyloxy)—6-methyl—, (6(α))—pregn-4-ene-3); availablefrom Wyeth-Ayerst under the tradenames Premphase and Prempro.

In general, a dosage of progestins may vary from about 0.05 mg to about10 mg or up to about 200 mg if microsized progesterone is administered.Examples of progestins include norethindrone; available from ESILederle, Inc., Philadelphia, Pa., under the tradename Aygestin, fromOrtho-McNeil under the tradename Micronor, and from Watson under thetradename Nor-QD; norgestrel; available from Wyeth-Ayerst under thetradename Ovrette; micronized progesterone (pregn-4-ene-3,20-dione);available from Solvay under the tradename Prometrium; andmedroxyprogesterone acetate; available from Pharmacia & Upjohn under thetradename Provera.

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more blood modifiers. Useful bloodmodifiers include but are not limited to anti-coagulants (argatroban,bivalirudin, dalteparin sodium, desirudin, dicumarol, lyapolate sodium,nafamostat mesylate, phenprocoumon, tinzaparin sodium, warfarin sodium);antithrombotic (anagrelide hydrochloride, bivalirudin, cilostazol,dalteparin sodium, danaparoid sodium, dazoxiben hydrochloride, efegatransulfate, enoxaparin sodium, fluretofen, ifetroban, ifetroban sodium,lamifiban, lotrafiban hydrochloride, napsagatran, orbofiban acetate,roxifiban acetate, sibrafiban, tinzaparin sodium, trifenagrel,abciximab, zolimomab aritox); fibrinogen receptor antagonists (roxifibanacetate, fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban,xemilofiban, monoclonal antibody 7E3, sibrafiban); platelet inhibitors(cilostazol, clopidogrel bisulfate, epoprostenol, epoprostenol sodium,ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulindae,idomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone,piroxicam, dipyridamole); platelet aggregation inhibitors (acadesine,beraprost, beraprost sodium, ciprostene calcium, itazigrel, lifarizine,lotrafiban hydrochloride, orbofiban acetate, oxagrelate, fradafiban,orbofiban, tirofiban, xemilofiban); hemorrheologic agents(pentoxifylline); lipoprotein associated coagulation inhibitor; FactorVIIa inhibitors (4H-31-benzoxazin-4-ones,4H-3,1-benzoxazin-4-thiones,quinazolin-4-ones, quinazolin-4-thiones, benzothiazin-4-ones,imidazolyl-boronic acid-derived peptide analogues TFPI-derived peptides,naphthalene-2-sulfonic acid{1-[3—(aminoiminomethyl)—benzyl]-2-oxo-pyrrolidin-3—(S)—yl}amidetrifluoroacetate, dibenzofuran-2-sulfonic acid{1-[3—(aminomethyl)—benzyl]-5-oxo-pyrrolidin-3-yl}-amide,tolulene-4-sulfonic acid{1-[3—(aminoiminomethyl)—benzyl]-2-oxo-pyrrolidin-3—(S)—yl}-amidetrifluoroacetate, 3,4-dihydro-1H-isoquinoline-2-sulfonic acid{1-[3—(aminoiminomethyl)—benzyl]-2-oxo-pyrrolin-3—(S)—yl}-amidetrifluoroacetate); Factor Xa inhibitors (disubstituted pyrazolines,disubstituted triazolines, substitutedn-[(aminoiminomethyl)phenyl]propylamides, substitutedn-[(aminomethyl)phenyl]propylamides, tissue factor pathway inhibitor(TFPI), low molecular weight heparins, heparinoids, benzimidazolines,benzoxazolinones, benzopiperazinones, indanones, dibasic (amidinoaryl)propanoic acid derivatives, amidinophenyl-pyrrolidines,amidinophenyl-pyrrolines, amidinophenyl-isoxazolidines, amidinoindoles,amidinoazoles, bis-arlysulfonylaminobenzamide derivatives, peptidicFactor Xa inhibitors).

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more cardiovascular agentsdifferent from the sterol absorption inhibitors discussed above. Usefulcardiovascular agents include but are not limited to calcium channelblockers (clentiazem maleate, amlodipine besylate, isradipine,nimodipine, felodipine, nilvadipine, nifedipine, teludipinehydrochloride, diltiazem hydrochloride, belfosdil, verapamilhydrochloride, fostedil); adrenergic blockers (fenspiride hydrochloride,labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol,acebutolol hydrochloride, alprenolol hydrochloride, atenolol, bunololhydrochloride, carteolol hydrochloride, celiprolol hydrochloride,cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranololhydrochloride, diacetolol hydrochloride, dilevalol hydrochloride,esmolol hydrochloride, exaprolol hydrochloride, flestolol sulfate,labetalol hydrochloride, levobetaxolol hydrochloride, levobunololhydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate,nadolol, pamatolol sulfate, penbutolol sulfate, practolol, propranololhydrochloride, sotalol hydrochloride, timolol, timolol maleate,tiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate,nebivolol); adrenergic stimulants; angiotensin converting enzyme (ACE)inhibitors (benazepril hydrochloride, benazeprilat, captopril, delaprilhydrochloride, fosinopril sodium, libenzapril, moexipril hydrochloride,pentopril, perindopril, quinapril hydrochloride, quinaprilat, ramipril,spirapril hydrochloride, spiraprilat, teprotide, enalapril maleate,lisinopril, zofenopril calcium, perindopril erbumine); antihypertensiveagents (althiazide, benzthiazide, captopril, carvedilol, chlorothiazidesodium, clonidine hydrochloride, cyclothiazide, delapril hydrochloride,dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium,guanfacine hydrochloride, methyldopa, metoprolol succinate, moexiprilhydrochloride, monatepil maleate, pelanserin hydrochloride,phenoxybenzamine hydrochloride, prazosin hydrochloride, primidolol,quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride,candesartan, candesartan cilexetil, telmisartan, amlodipine besylate,amlodipine maleate, bevantolol hydrochloride); angiotensin II receptorantagonists (candesartan, irbesartan, losartan potassium, candesartancilexetil, telmisartan); anti-anginal agents (amlodipine besylate,amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride,butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprololsuccinate, molsidomine, monatepil maleate, primidolol, ranolazinehydrochoride, tosifen, verapamil hydrochloride); coronary vasodilators(fostedil, azaclorzine hydrochloride, chromonar hydrochloride,clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine,erythrityl tetranitrate, isosorbide dinitrate, isosorbide mononitrate,lidoflazine, mioflazine hydrochloride, mixidine, molsidomine,nicorandil, nifedipine, nisoldipine, nitroglycerine, oxprenololhydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propatylnitrate, terodiline hydrochloride, tolamolol, verapamil); diuretics (thecombination product of hydrochlorothiazide and spironolactone and thecombination product of hydrochlorothiazide and triamterene).

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more antidiabetic medications forreducing blood glucose levels in a human. Useful antidiabeticmedications include, but are not limited to, drugs that reduce energyintake or suppress appetite, drugs that increase energy expenditure andnutrient-partitioning agents. Suitable antidiabetic medications include,but are not limited to, sulfonylurea (such as acetohexamide,chlorpropamide, gliamilide, gliclazide, glimepiride, glipizide,glyburide, glibenclamide, tolazamide, and tolbutamide), meglitinide(such as repaglinide and nateglinide), biguanide (such as metformin andbuformin), thiazolidinedione (such as troglitazone, rosiglitazone,pioglitazone, ciglitazone, englitazone, and darglitazone),alpha-glucosidase inhibitor (such as acarbose, miglitol, camiglibose,and voglibose), certain peptides (such as amlintide, pramlintide,exendin, and GLP-1 agonistic peptides), and orally administrable insulinor insulin composition for intestinal delivery thereof. Generally, atotal dosage of the above-described antidiabetic medications can rangefrom 0.1 to 1,000 mg/day in single or 2–4 divided doses.

Mixtures of any of the pharmacological or therapeutic agents describedabove can be used in the compositions and therapeutic combinations ofthese other embodiments of the present invention.

In another embodiment, a method of treating or preventing obesity isprovided comprising the step of administering to a subject in need ofsuch treatment an effective amount of a composition comprising at leastone sterol absorption inhibitor and/or at least one 5α-stanol absorptioninhibitor.

In another embodiment, a method of treating or preventing obesity isprovided comprising the step of administering to a subject in need ofsuch treatment an effective amount of a composition comprising at leastone sterol and/or 5α-stanol absorption inhibitor represented by Formula(II) below:

The compositions and therapeutic combinations of the present inventioncan be administered to a subject in need of such treatment in atherapeutically effective amount to treat vascular conditions and/orobesity. The compositions and treatments can be administered by anysuitable means that produce contact of these compounds with the site ofaction in the body, for example in the plasma, liver or small intestineof a subject.

The daily dosage for the various compositions and therapeuticcombinations described above can be administered to a subject in asingle dose or in multiple subdoses, as desired. Subdoses can beadministered 2 to 6 times per day, for example. Sustained releasedosages can be used. Where the obesity control medication(s) and sterolabsorption inhibitor(s) are administered in separate dosages, the numberof doses of each component given per day may not necessarily be thesame, e.g., one component may have a greater duration of activity andwill therefore need to be administered less frequently.

The compositions, therapeutic combinations or medicaments of the presentinvention can further comprise one or more pharmaceutically acceptablecarriers, one or more excipients and/or one or more additives. Thepharmaceutical compositions can comprise about 1 to about 99 weightpercent of active ingredient (one or more compounds of Formula I–XII),and preferably about 5 to about 95 percent active ingredient.

Useful pharmaceutically acceptable carriers can be either solid, liquidor gas. Non-limiting examples of pharmaceutically acceptable carriersinclude solids and/or liquids such as magnesium carbonate, magnesiumstearate, talc, sugar, lactose, ethanol, glycerol, water and the like.The amount of carrier in the treatment composition or therapeuticcombination can range from about 5 to about 99 weight percent of thetotal weight of the treatment composition or therapeutic combination.Non-limiting examples of suitable pharmaceutically acceptable excipientsand additives include non-toxic compatible fillers, binders such asstarch, polyvinyl pyrrolidone or cellulose ethers, disintegrants such assodium starch glycolate, crosslinked polyvinyl pyrrolidone orcroscarmellose sodium, buffers, preservatives, anti-oxidants,lubricants, flavorings, thickeners, coloring agents, wetting agents suchas sodium lauryl sulfate, emulsifiers and the like. The amount ofexcipient or additive can range from about 0.1 to about 95 weightpercent of the total weight of the treatment composition or therapeuticcombination. One skilled in the art would understand that the amount ofcarrier(s), excipients and additives (if present) can vary. Furtherexamples of pharmaceutically acceptable carriers and methods ofmanufacture for various compositions can be found in A. Gennaro (ed.),Remington: The Science and Practice of Pharmacy, 20^(th) Edition,(2000), Lippincott Williams & Wilkins, Baltimore, Md.

Useful solid form preparations include powders, tablets, dispersiblegranules, capsules, cachets and suppositories. An example of apreparation of a preferred solid form dosage formulation is providedbelow.

Useful liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also useful are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

In another embodiment, the present invention provides the use of atleast one compound represented by Formulae (I–XII) for manufacture of amedicament (such as one of the compositions discussed above) for thetreatment of obesity.

The following formulation exemplifies one of the dosage forms of thisinvention. In the formulation, the term “Active Compound I” designates asterol or 5α-stanol absorption inhibitor such as any of the compounds ofFormulas I–XII described herein above and the term “Active Compound II”designates an obesity control medication described herein above.

EXAMPLE

Tablets No. Ingredient mg/tablet 1 Active Compound I 10 2 Lactosemonohydrate NF 55 3 Microcrystalline cellulose NF 20 4 Povidone USP(K29-32) 4 5 Croscarmellose sodium NF 8 6 Sodium lauryl sulfate NF 2 7Magnesium stearate NF 1 Total 100

In the present invention, the above-described tablet can becoadministered with a tablet, capsule, etc. comprising a dosage ofActive Compound II, for example an obesity control medication asdescribed above.

Method of Manufacture

Mix Item No. 4 with purified water in suitable mixer to form bindersolution. Spray the binder solution and then water over Items 1, 2 and 6and a portion of item 5 in a fluidized bed processor to granulate theingredients. Continue fluidization to dry the damp granules. Screen thedried granule and blend with Item No. 3 and the remainder of Item No. 5.Add Item No. 7 and mix. Compress the mixture to appropriate size andweight on a suitable tablet machine.

For coadministration in separate tablets or capsules, representativeformulations comprising a sterol or 5α-stanol absorption inhibitor suchas are discussed above are well known in the art and representativeformulations comprising an obesity control medication such as arediscussed above are well known in the art. It is contemplated that wherethe two active ingredients are administered as a single composition, thedosage forms disclosed above for sterol or 5α-stanol absorptioninhibitor may readily be modified using the knowledge of one skilled inthe art.

Since the present invention relates to controlling obesity and/orreducing the plasma sterol (especially cholesterol) or 5α-stanolconcentrations or levels by treatment with a combination of activeingredients wherein the active ingredients may be administeredseparately, the invention also relates to combining separatepharmaceutical compositions in kit form. That is, a kit is contemplatedwherein two separate units are combined: a pharmaceutical compositioncomprising at least one obesity control medication and a separatepharmaceutical composition comprising at least one sterol absorptioninhibitor as described above. The kit will preferably include directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components must beadministered in different dosage forms (e.g., oral and parenteral) orare administered at different dosage intervals.

The treatment compositions and therapeutic combinations of the presentinvention can inhibit the intestinal absorption of cholesterol insubjects and can be useful in the treatment and/or prevention ofvascular conditions, such as vascular inflammation, atherosclerosis,hypercholesterolemia and sitosterolemia, stroke, obesity and lowering ofplasma levels of cholesterol in subjects, in particular in humans.

In another embodiment of the present invention, the compositions andtherapeutic combinations of the present invention can reduce plasmaconcentration of at least one sterol selected from the group consistingof cholesterol and phytosterols (such as sitosterol, campesterol,stigmasterol and avenosterol), or 5α-stanols (such as cholestanol,5α-campestanol, 5α-sitostanol), and mixtures thereof. The plasmaconcentration can be reduced by administering to a subject in need ofsuch treatment an effective amount of at least one treatment compositioncomprising at least one sterol and/or 5α-stanol absorption inhibitordescribed above or a treatment composition or therapeutic combinationcomprising at least one obesity control medication and at least onesterol and/or 5α-stanol absorption inhibitor described above. Thereduction in plasma concentration of sterols can range from about 1 toabout 70 percent, and preferably about 10 to about 50 percent. Methodsof measuring serum total blood cholesterol and total LDL cholesterol arewell known to those skilled in the art and for example include thosedisclosed in PCT WO 99/38498 at page 11, incorporated by referenceherein. Methods of determining levels of other sterols in serum aredisclosed in H. Gylling et al., “Serum Sterols During Stanol EsterFeeding in a Mildly Hypercholesterolemic Population”, J. Lipid Res. 40:593–600 (1999), incorporated by reference herein.

Illustrating the preparation of a compound of Formula II is thefollowing example which, however, is not to be considered as limitingthe invention to their details. Unless otherwise indicated, all partsand percentages in the following examples, as well as throughout thespecification, are by weight.

EXAMPLE Preparation of Compound of Formula (II)

Step 1): To a solution of (S)—4-phenyl-2-oxazolidinone (41 g, 0.25 mol)in CH₂Cl₂ (200 ml), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol)and triethylamine (84.7 ml, 0.61 mol) and the reaction mixture wascooled to 0° C. Methyl-4—(chloroformyl)butyrate (50 g, 0.3 mol) wasadded as a solution in CH₂Cl₂ (375 ml) dropwise over 1 h, and thereaction was allowed to warm to 22° C. After 17 h, water and H₂SO₄ (2N,100 ml), was added the layers were separated, and the organic layer waswashed sequentially with NaOH (10%), NaCl (sat'd) and water. The organiclayer was dried over MgSO₄ and concentrated to obtain a semicrystallineproduct.

Step 2): To a solution of TiCl₄ (18.2 ml, 0.165 mol) in CH₂Cl₂ (600 ml)at 0° C., was added titanium isopropoxide (16.5 ml, 0.055 mol). After 15min, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution inCH₂Cl₂ (100 ml). After 5 min., diisopropylethylamine (DIPEA) (65.2 ml,0.37 mol) was added and the reaction mixture was stirred at 0° C. for 1h, the reaction mixture was cooled to −20° C., and4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added asa solid. The reaction mixture was stirred vigorously for 4 h at −20° C.,then acetic acid was added as a solution in CH₂Cl₂ dropwise over 15 min,the reaction mixture was allowed to warm to 0° C., and H₂SO₄ (2N) wasadded. The reaction mixture was stirred an additional 1 h, the layerswere separated, washed with water, separated and the organic layer wasdried. The crude product was crystallized from ethanol/water to obtainthe pure intermediate.

Step 3): To a solution of the product of Step 2 (8.9 g, 14.9 mmol) intoluene (100 ml) at 50° C., was added N,O-bis(trimethylsilyl)acetamide(BSA) (7.50 ml, 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol)was added and the reaction mixture stirred at 50° C. for an additional 3h. The reaction mixture was cooled to 22° C., CH₃OH (10 ml), was added.The reaction mixture was washed with HCl (1N), NaHCO₃ (1N) and NaCl(sat'd.), and the organic layer was dried over MgSO₄.

Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) inCH₃OH (3 ml), was added water (1 ml) and LiOH·H₂O (102 mg, 2.4 mmole).The reaction mixture was stirred at 22° C. for 1 h and then additionalLiOH·H₂O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCl (1N)and EtOAc was added, the layers were separated, the organic layer wasdried and concentrated in vacuo. To a solution of the resultant product(0.91 g, 2.2 mmol) in CH₂Cl₂ at 22° C., was added ClCOCOCl (0.29 ml, 3.3mmol) and the mixture stirred for 16 h. The solvent was removed invacuo.

Step 5): To an efficiently stirred suspension of 4-fluorophenylzincchloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1M inTHF, 4.4 ml, 4.4 mmol) and ZnCl₂ (0.6 g, 4.4 mmol) at 4° C., was addedtetrakis(triphenyl-phosphine)palladium (0.25 g, 0.21 mmol) followed bythe product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml).The reaction was stirred for 1 h at 0° C. and then for 0.5 h at 22° C.HCl (1N, 5 ml) was added and the mixture was extracted with EtOAc. Theorganic layer was concentrated to an oil and purified by silica gelchromatography to obtain1—(4-fluorophenyl)—4(S)—(4-hydroxyphenyl)—3(R)—(3-oxo-3-phenylpropyl)—2-azetidinone:HRMS calc'd for C₂₄H₁₉F₂NO₃=408.1429, found 408.1411.

Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 ml), wasadded(R)—tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole(120 mg, 0.43 mmol) and the mixture was cooled to −20° C. After 5 min,borohydride-dimethylsulfide complex (2M in THF, 0.85 ml, 1.7 mmol) wasadded dropwise over 0.5 h. After a total of 1.5 h , CH₃OH was addedfollowed by HCl (1 N) and the reaction mixture was extracted with EtOActo obtain1—(4-fluorophenyl)—3(R)—[3(S)—(4-fluorophenyl)—3-hydroxypropyl)]-4(S)—[4—(phenylmethoxy)phenyl]-2-azetidinone(compound 6A-1) as an oil. ¹H in CDCl₃ d H3=4.68. J=2.3 Hz. Cl (M⁺H)500.

Use of(S)—tetra-hydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborolegives the corresponding 3(R)—hydroxypropyl azetidinone (compound 6B-1).¹H in CDCl₃ d H3=4.69. J=2.3 Hz. Cl (M⁺H) 500.

To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 ml), wasadded 10% Pd/C (0.03 g) and the reaction mixture was stirred under apressure (60 psi) of H₂ gas for 16 h. The reaction mixture was filteredand the solvent was concentrated to obtain compound 6A. Mp 164–166° C.;Cl (M⁺H) 410. [α]_(D) ²⁵=−28.1° (c 3, CH₃OH). Elemental analysis calc'dfor C₂₄H₂₁F₂NO₃: C, 70.41; H, 5.17; N, 3.42; found C, 70.25; H, 5.19; N,3.54.

Similarly treat compound 6B-1 to obtain compound 6B. Mp 129.5–132.5° C.;Cl (M⁺H) 410. Elemental analysis calc'd for C₂₄H₂₁ F₂NO₃: C, 70.41; H,5.17; N, 3.42; found C, 70.30; H, 5.14; N, 3.52.

Step 6′ (Alternative): To a solution of the product of Step 5 (0.14 g,0.3 mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g) and thereaction was stirred under a pressure (60 psi) of H₂ gas for 16 h. Thereaction mixture was filtered and the solvent was concentrated to afforda 1:1 mixture of compounds 6A and 6B.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications that are within the spirit and scopeof the invention, as defined by the appended claims.

1. A composition comprising: (a) at least one obesity controlmedication; and (b) at least one sterol absorption inhibitor or at leastone 5α-stanol absorption inhibitor or a pharmaceutically acceptable saltthereof or a solvate thereof.
 2. The composition according to claim 1,wherein the at least one sterol or 5α-stanol absorption inhibitor isrepresented by Formula (I):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein: Ar¹ and Ar² are independently selected from the groupconsisting of aryl and R⁴-substituted aryl; Ar³ is aryl orR⁵-substituted aryl; X, Y and Z are independently selected from thegroup consisting of —CH₂—, —CH(lower alkyl)—and —C(dilower alkyl)—; Rand R² are independently selected from the group consisting of —OR⁶,—O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷; R¹ and R³ are independentlyselected from the group consisting of hydrogen, lower alkyl and aryl; qis 0 or 1; r is 0 or 1; m, n and p are independently selected from 0, 1,2, 3 or 4; provided that at least one of q and r is 1, and the sum of m,n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and ris 1, the sum of m, q and n is 1, 2, 3, 4 or 5; R⁴ is 1–5 substituentsindependently selected from the group consisting of lower alkyl, —OR₆,—O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷,—NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, —(loweralkylene)COOR⁶, —CH═CH—COOR⁶, —CF₃, —CN, —NO₂ and halogen; R⁵ is 1–5substituents independently selected from the group consisting of —OR⁶,—O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷,—NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, —(loweralkylene)COOR⁶ and —CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independentlyselected from the group consisting of hydrogen, lower alkyl, aryl andaryl-substituted lower alkyl; and R⁹ is lower alkyl, aryl oraryl-substituted lower alkyl.
 3. The composition according to claim 2,wherein the sterol or 5α-stanol absorption inhibitor is represented byFormula (II) below:


4. The composition according to claim 1, wherein the at least one sterolabsorption inhibitor is represented by Formula (III):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (III) above: Ar¹ is R³-substituted aryl; Ar² isR⁴-substituted aryl; Ar³ is R⁵-substituted aryl; Y and Z areindependently selected from the group consisting of —CH₂—, —CH(loweralkyl)— and —C(dilower alkyl)—; A is selected from —O—, —S—, —S(O)— or—S(O)₂—; R¹ is selected from the group consisting of —OR⁶, —O(CO)R⁶,—O(CO)OR⁹ and —O(CO)NR⁶R⁷; R² is selected from the group consisting ofhydrogen, lower alkyl and aryl; or R¹ and R² together are ═O; q is 1, 2or 3; p is 0, 1, 2, 3 or 4; R⁵ is 1–3 substituents independentlyselected from the group consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CH₂)₁₋₅OR⁹, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹,—NR⁶(CO)NR⁷R⁸, —NR⁶SO₂-lower alkyl, —NR⁶SO₂-aryl, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂-alkyl, S(O)₀₋₂-aryl, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, o-halogeno, m-halogeno, o-lower alkyl, m-loweralkyl, —(lower alkylene)—COOR⁶, and —CH═CH—COOR⁶; R³ and R⁴ areindependently 1–3 substituents independently selected from the groupconsisting of R⁵, hydrogen, p-lower alkyl, aryl, —NO₂, —CF₃ andp-halogeno; R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; and R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl. 5.The composition according to claim 1, wherein the at least one sterolabsorption inhibitor is represented by Formula (IV):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (IV) above: A is selected from the group consistingof R²-substituted heterocycloalkyl, R²-substituted heteroaryl,R²-substituted benzofused heterocycloalkyl, and R²-substitutedbenzofused heteroaryl; Ar¹ is aryl or R³-substituted aryl; Ar² is arylor R⁴-substituted aryl; Q is a bond or, with the 3-position ring carbonof the azetidinone, forms the spiro group

R¹ is selected from the group consisting of: —(CH₂)_(q)—, wherein q is2–6, provided that when Q forms a spiro ring, q can also be zero or 1;—(CH₂)_(e)—G—(CH₂)_(r)—, wherein G is —O—, —C(O)—, phenylene, —NR⁸— or—S(O)₀₋₂—, e is 0–5 and r is 0–5, provided that the sum of e and r is1–6; —(C₂–C₆ alkenylene)—; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃–C₆ cycloalkylene, f is 1–5 and g is 0–5, provided that the sum of fand g is 1–6; R⁵ is selected from:

R⁶ and R⁷ are independently selected from the group consisting of —CH₂—,—CH(C₁–C₆ alkyl)—, —C(di-(C₁–C₆)alkyl), —CH═CH— and —C(C₁–C₆ alkyl)═CH—;or R⁵ together with an adjacent R⁶, or R⁵ together with an adjacent R⁷,form a —CH═CH— or a —CH═C(C₁–C₆ alkyl)—group; a and b are independently0, 1, 2 or 3, provided both are not zero; provided that when R⁶ is—CH═CH— or —C(C₁–C₆ alkyl)═CH—, a is 1; provided that when R⁷ is —CH═CH—or —C(C₁–C₆ alkyl)═CH—, b is 1; provided that when a is 2 or 3, the R⁶'scan be the same or different; and provided that when b is 2 or 3, theR⁷'s can be the same or different; and when Q is a bond, R¹ also can beselected from:

where M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independentlyselected from the group consisting of —CH₂—, —CH(C₁–C₆ alkyl)— and—C(di-(C₁–C₆)alkyl); R¹⁰ and R¹² are independently selected from thegroup consisting of —OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶ and —O(CO)NR¹⁴R¹⁵; R¹¹and R¹³are independently selected from the group consisting of hydrogen,(C₁–C₆)alkyl and aryl; or R¹⁰ and R¹¹ together are ═O, or R¹² andR¹³together are ═O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; tis 0 or 1; m, n and p are independently 0–4; provided that at least oneof s and t is 1, and the sum of m, n, p, s and t is 1–6; provided thatwhen p is 0 and t is 1, the sum of m, s and n is 1–5; and provided thatwhen p is 0 and s is 1, the sum of m, t and n is 1–5; v is 0 or 1; j andk are independently 1–5, provided that the sum of j, k and v is 1–5; R²is 1–3 substituents on the ring carbon atoms selected from the groupconsisting of hydrogen, (C₁–C₁₀)alkyl, (C₂–C₁₀)alkenyl, (C₂–C₁₀)alkynyl,(C₃–C₆)cycloalkyl, (C₃–C₆)cycloalkenyl, R¹⁷-substituted aryl,R¹⁷-substituted benzyl, R¹⁷-substituted benzyloxy, R¹⁷-substitutedaryloxy, halogeno, —NR¹⁴R¹⁵, NR¹⁴R¹⁵(C₁–C₆ alkylene)—, NR¹⁴R¹⁵C(O)(C₁–C₆alkylene)—, —NHC(O)R¹⁶, OH C₁–C₆ alkoxy, —OC(O)R¹⁶, —COR¹⁴,hydroxy(C₁–C₆)alkyl, (C₁–C₆)alkoxy(C₁–C₆)alkyl, NO₂, —S(O)₀₋₂R¹⁶,—SO₂NR¹⁴R¹⁵ and —(C₁–C₆ alkylene)COOR¹⁴; when R² is a substituent on aheterocycloalkyl ring, R² is as defined, or is ═O or

where R² is a substituent on a substitutable ring nitrogen, it ishydrogen, (C₁–C₆)alkyl, aryl, (C₁–C₆)alkoxy, aryloxy,(C₁–C₆)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH₂)₁₋₆CONR¹⁸R¹⁸,

wherein J is —O—, —NH—, —NR¹⁸— or —CH₂—; R³ and R⁴ are independentlyselected from the group consisting of 1–3 substituents independentlyselected from the group consisting of (C₁–C₆)alkyl, —OR¹⁴, —O(CO)R¹⁴,—O(CO)OR¹⁶, —O(CH₂)₁₋₅OR¹⁴, —O(CO)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴(CO)R¹⁵,—NR¹⁴(CO)OR¹⁶, —NR¹⁴(CO)NR¹⁵R¹⁹, —NR¹⁴SO₂R¹⁶, —COOR¹⁴, —CONR¹⁴R¹⁵,—COR¹⁴, —SO₂NR¹⁴R¹⁵, S(O)₀₋₂R¹⁶, —O(CH₂)₁₋₁₀—COOR¹⁴,—O(CH₂)₁₋₁₀CONR¹⁴R¹⁵, —(C₁–C₆ alkylene)—COOR¹⁴, —CH═CH—COOR¹⁴, —CF₃,—CN,—NO₂ and halogen; R⁸ is hydrogen, (C₁–C₆)alkyl, aryl (C₁–C₆)alkyl,—C(O)R¹⁴ or —COOR¹⁴; R⁹ and R¹⁷are independently 1–3 groupsindependently selected from the group consisting of hydrogen,(C₁–C₆)alkyl, (C₁–C₆)alkoxy, —COOH, NO₂, —NR¹⁴R¹⁵, OH and halogeno; R¹⁴and R¹⁵ are independently selected from the group consisting ofhydrogen, (C₁–C₆)alkyl, aryl and aryl-substituted (C₁–C₆)alkyl; R¹⁶ is(C₁–C₆)alkyl, aryl or R¹⁷-substituted aryl; R¹⁸ is hydrogen or(C₁–C₆)alkyl; and R¹⁹ is hydrogen, hydroxy or (C₁–C₆)alkoxy.
 6. Thecomposition according to claim 1, wherein the at least one sterolabsorption inhibitor is represented by Formula (V):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (V) above: Ar¹ is aryl, R¹⁰-substituted aryl orheteroaryl; Ar² is aryl or R⁴-substituted aryl; Ar³ is aryl orR⁵-substituted aryl; X and Y are independently selected from the groupconsisting of —CH₂—, —CH(lower alkyl)— and —C(dilower alkyl)—; R is—OR⁶, —O(CO)R⁶, —O(CO)OR⁹ or —O(CO)NR⁶R⁷; R¹ is hydrogen, lower alkyl oraryl; or R and R¹ together are ═O; q is 0 or 1; r is 0, 1 or 2; m and nare independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n andq is 1, 2, 3, 4 or 5; R⁴ is 1–5 substituents independently selected fromthe group consisting of lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹,—NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹,—O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, —(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁵ is 1–5 substituents independently selected from thegroup consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂, halogen, —(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and R¹⁰is 1–5 substituents independently selected from the group consisting oflower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, —S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂ and halogen.
 7. The compositionaccording to claim 1, where the at least one sterol absorption inhibitoris represented by Formula (VI):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein: R₁ is

R₂ and R₃ are independently selected from the group consisting of:—CH₂—, —CH(lower alkyl)—, —C(di-lower alkyl)—, —CH═CH— and —C(loweralkyl)═CH—; or R₁ together with an adjacent R₂, or R₁ together with anadjacent R₃, form a —CH═CH— or a —CH═C(lower alkyl)— group; u and v areindependently 0, 1, 2 or 3, provided both are not zero; provided thatwhen R₂ is —CH═CH— or —C(lower alkyl)═CH—, v is 1; provided that when R₃is —CH═CH— or —C(lower alkyl)═CH—, u is 1; provided that when v is 2 or3, the R₂'s can be the same or different; and provided that when u is 2or 3, the R₃'s can be the same or different; R₄ is selected fromB—(CH₂)_(m)C(O)—, wherein m is 0, 1, 2, 3, 4 or 5; B—(CH₂)_(q)—, whereinq is 0, 1, 2, 3, 4, 5 or 6; B—(CH₂)_(e)—Z—(CH₂)_(r)—, wherein Z is —O—,—C(O)—, phenylene, —N(R₈)—or —S(O)₀₋₂—, e is 0, 1, 2, 3, 4 or 5 and r is0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5or 6; B—(C₂–C₆ alkenylene)—; B—(C₄–C₆ alkadienylene)—;B—(CH₂)_(t)—Z—(C₂–C₆ alkenylene)—, wherein Z is as defined above, andwherein t is 0, 1, 2 or 3, provided that the sum of t and the number ofcarbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6; B—(CH₂)_(f) 13V—(CH₂)_(g)—, wherein V is C₃–C₆ cycloalkylene, f is 1, 2, 3, 4 or 5 andg is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4,5 or 6; B—(CH₂)_(t)—V—(C₂–C₆ alkenylene)— or B—(C₂–C₆alkenylene)—V—(CH₂)_(t)—, wherein V and t are as defined above, providedthat the sum of t and the number of carbon atoms in the alkenylene chainis 2, 3, 4, 5 or 6; B—(CH₂)_(a)—Z—(CH₂)_(b)—V—(CH₂)_(d)—, wherein Z andV are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; orT—(CH₂)_(s)—, wherein T is cycloalkyl of 3–6 carbon atoms and s is 0, 1,2, 3, 4, 5 or 6; or R₁ and R₄ together form the group

B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,heteroaryl or W-substituted beteroaryl, wherein heteroaryl is selectedfrom the group consisting of pyrrolyl, pyridinyl, pyrimidinyl,pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl,oxazolyl and furanyl, and for nitrogen-containing heteroaryls, theN-oxides thereof, or

W is 1 to 3 substituents independently selected from the groupconsisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (loweralkoxyimino)—lower alkyl, lower alkanedioyl, lower alkyl loweralkanedioyl, allyloxy, —CF₃, —OCF₃, benzyl, R₇-benzyl, benzyloxy,R₇-benzyloxy, phenoxy, R₇-phenoxy, dioxolanyl, NO₂, —N(R₈)(R₉),N(R₈)(R₉)—lower alkylene—, N(R₈)(R₉)—lower alkylenyloxy—, OH, halogeno,—CN, —N₃, —NHC(O)OR₁₀, —NHC(O)R₁₀, R₁₁O₂SNH—, (R₁₁O₂S)₂N—, —S(O)₂NH₂,—S(O)₀₋₂R₈, tert-butyldimethyl-silyloxymethyl, —C(O)R₁₂, —COOR₁₉,—CON(R₈)(R₉), —CH═CHC(O)R₁₂, —lower alkylene—C(O)R₁₂, R₁₀C(O)(loweralkylenyloxy)—, N(R₈)(R₉)C(O)(lower alkylenyloxy)— and

for substitution on ring carbon atoms, and the substituents on thesubstituted heteroaryl ring nitrogen atoms, when present, are selectedfrom the group consisting of lower alkyl, lower alkoxy, —C(O)OR₁₀,—C(O)R₁₀, OH, N(R₈)(R₉)—lower alkylene—, N(R₈)(R₉)—lower alkylenyloxy—,—S(O)₂NH₂ and 2—(trimethylsilyl )—ethoxymethyl; R₇ is 1–3 groupsindependently selected from the group consisting of lower alkyl, loweralkoxy, —COOH, NO₂, —N(R₈)(R₉), OH, and halogeno; R₈ and R₉ areindependently selected from H or lower alkyl; R₁₀ is selected from loweralkyl, phenyl, R₇-phenyl, benzyl or R₇-benzyl; R₁₁ is selected from OH,lower alkyl, phenyl, benzyl, R₇-phenyl or R₇-benzyl; R₁₂ is selectedfrom H, OH, alkoxy, phenoxy, benzyloxy,

—N(R₈)(R₉), lower alkyl, phenyl or R₇-phenyl; R₁₃is selected from —O—,—CH₂—, —NH—, —N(lower alkyl)— or —NC(O)R₁₉; R₁₅, R₁₆ and R₁₇areindependently selected from the group consisting of H and the groupsdefined for W; or R₁₅ is hydrogen and R₁₆ and R₁₇, together withadjacent carbon atoms to which they are attached, form a dioxolanylring; R₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and R₂₀ andR₂₁ are independently selected from the group consisting of phenyl,W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl,indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substitutedheteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryland cyclopropyl, wherein heteroaryl is as defined above.
 8. Thecomposition according to claim 1, wherein the at least one sterolabsorption inhibitor is represented by Formula (VIIA) or (VIIB):

or a pharmaceutically acceptable salt or solvate thereof, wherein: A is—CH═CH—, —C≡C— or —(CH₂)_(p)— wherein p is 0, 1 or 2; B is

D is —(CH₂)_(m)C(O)—or —(CH₂)_(q)— wherein m is 1, 2, 3 or 4 and q is 2,3 or 4; E is C₁₀ to C₂₀ alkyl or —C(O)—(C₉ to C₁₉)—alkyl, wherein thealkyl is straight or branched, saturated or containing one or moredouble bonds; R is hydrogen, C₁–C₁₅ alkyl, straight or branched,saturated or containing one or more double bonds, or B—(CH₂)_(r)—,wherein r is 0, 1, 2, or 3; R₁, R₂, R₃, R₁′, R₂′, and R₃′ areindependently selected from the group consisting of hydrogen, loweralkyl, lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino,dilower alkylamino, —NHC(O)OR₅, R₆O₂SNH— and —S(O)₂NH₂; R₄ is

wherein n is 0, 1, 2 or 3; R₅ is lower alkyl; and R₆ is OH, lower alkyl,phenyl, benzyl or substituted phenyl wherein the substituents are 1–3groups independently selected from the group consisting of lower alkyl,lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino anddilower alkylamino.
 9. The composition according to claim 1, wherein theat least one sterol absorption inhibitor is represented by Formula(VIII):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (VIII) above, R²⁶ is H or OG¹; G and G¹ areindependently selected from the group consisting of

provided that when R²⁶ is H or OH, G is not H; R, R^(a) and R^(b) areindependently selected from the group consisting of H, —OH, halogeno,—NH₂, azido, (C₁–C₆)alkoxy(C₁–C₆)—alkoxy or —W—R³⁰; W is independentlyselected from the group consisting of —NH—C(O)—, —O—C(O)—,—O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)—and —O—C(S)—N(R³¹)—; R² and R⁶ areindependently selected from the group consisting of H, (C₁–C₆)alkyl,aryl and aryl(C₁–C₆)alkyl; R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) areindependently selected from the group consisting of H, (C₁–C₆)alkyl,aryl(C₁–C₆)alkyl, —C(O)(C₁–C₆)alkyl and —C(O)aryl; R³⁰ is selected fromthe group consisting of R³²-substituted T,R³²-substituted—T—(C₁–C₆)alkyl, R³²-substituted—(C₂–C₄)alkenyl,R³²-substituted—(C₁–C₆)alkyl, R³²-substituted—(C₃–C₇)cycloalkyl andR³²-substituted—(C₃–C₇)cycloalkyl(C₁–C₆)alkyl; R³¹ is selected from thegroup consisting of H and (C₁–C₄)alkyl; T is selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl,imidazolyl and pyridyl; R³² is independently selected from 1–3substituents independently selected from the group consisting ofhalogeno, (C₁–C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁–C₄)alkoxy,methylenedioxy, oxo, (C₁–C₄)alkylsulfanyl, (C₁–C₄)alkylsulfinyl,(C₁–C₄)alkylsulfonyl, —N(CH₃)₂, —C(O)—NH(C₁–C₄)alkyl,—C(O)—N((C₁–C₄)alkyl)₂, —C(O)—(C₁–C₄)alkyl, —C(O)—(C₁–C₄)alkoxy andpyrrolidinylcarbonyl; or R³² is a covalent bond and R³¹, the nitrogen towhich it is attached and R³² form a pyrrolidinyl, piperidinyl,N-methyl-piperazinyl, indolinyl or morpholinyl group, or a(C₁–C₄)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl,N-methylpiperazinyl, indolinyl or morpholinyl group; Ar¹ is aryl orR¹⁰-substituted aryl; Ar² is aryl or R¹¹-substituted aryl; Q is a bondor, with the 3-position ring carbon of the azetidinone, forms the spirogroup

R¹ is selected from the group consisting of —(CH₂)_(q)—, wherein q is2–6, provided that when Q forms a spiro ring, q can also be zero or 1;—(CH₂)_(e)—E—(CH₂)_(r), wherein E is —O—, —C(O)—, phenylene, —NR²²— or—S(O)₀₋₂—, e is 0–5 and r is 0–5, provided that the sum of e and r is1–6; —(C₂–C₆)alkenylene—; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃–C₆ cycloalkylene, f is 1–5 and g is 0–5, provided that the sum of fand g is 1–6; R¹² is

R¹³and R¹⁴ are independently selected from the group consisting of—CH₂—, —CH(C₁–C₆ alkyl)—, —C(di-(C₁–C₆) alkyl), —CH═CH— and —C(C₁–C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁–C₆ alkyl)— group; a and bare independently 0, 1, 2 or 3, provided both are not zero; providedthat when R¹³is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, a is 1; provided thatwhen R¹⁴ is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, b is 1; provided that when ais 2 or 3, the R¹³'s can be the same or different; and provided thatwhen b is 2 or 3, the R¹⁴'s can be the same or different; and when Q isa bond, R¹ also can be:

M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independently selectedfrom the group consisting of —CH₂—, —CH(C₁–C₆)alkyl— and—C(di-(C₁–C₆)alkyl); R¹⁰ and R¹¹ are independently selected from thegroup consisting of 1–3 substituents independently selected from thegroup consisting of (C₁–C₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹,—O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹,—NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰,S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁–C₆alkylene)—COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halogen; R¹⁵ andR¹⁷ are independently selected from the group consisting of —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹ and —O(CO)NR¹⁹R²⁰; R¹⁶ and R¹⁸ are independentlyselected from the group consisting of H, (C₁–C₆)alkyl and aryl; or R¹⁵and R¹⁶ together are ═O, or R¹⁷and R¹⁸ together are ═O; d is 1, 2 or 3;h is 0, 1, 2, 3 or 4; S is 0 or 1; t is 0 or 1; m, n and p areindependently 0–4; provided that at least one of s and t is 1, and thesum of m, n, p, s and t is 1–6; provided that when p is 0 and t is 1,the sum of m, s and n is 1–5; and provided that when p is 0 and s is 1,the sum of m, t and n is 1–5; v is 0 or 1; j and k are independently1–5, provided that the sum of j, k and v is 1–5; and when Q is a bondand R¹ is

Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are independently selected from the group, consisting of H,(C₁–C₆)alkyl, aryl and aryl-substituted (C₁–C₆)alkyl; R²¹ is(C₁–C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁–C₆)alkyl, aryl(C₁–C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are independently 1–3groups independently selected from the group consisting of H,(C₁–C₆)alkyl, (C₁–C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halogeno; andR²⁵ is H, —OH or (C₁–C₆)alkoxy.
 10. The composition according to claim1, wherein the at least one sterol absorption inhibitor is representedby Formula (IX):

or a pharmaceutically acceptable salt or solvate thereof, wherein inFormula (IX): R¹ is selected from the group consisting of H, G, G¹, G²,—SO₃H and —PO₃H; G is selected from the group consisting of: H,

wherein R, R^(a) and R^(b) are each independently selected from thegroup consisting of H, —OH, halo, —NH₂, azido,(C₁–C₆)alkoxy(C₁–C₆)alkoxy or —W—R³⁰; W is independently selected fromthe group consisting of —NH—C(O)—, —O—C(O)—, —O—C(O)—N(R³¹)—,—NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R² and R⁶ are each independentlyselected from the group consisting of H, (C₁–C₆)alkyl, acetyl, aryl andaryl(C₁–C₆)alkyl; R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) are eachindependently selected from the group consisting of H, (C₁–C₆)alkyl,acetyl, aryl(C₁–C₆)alkyl, —C(O)(C₁–C₆)alkyl and —C(O)aryl; R³⁰ isindependently selected from the group consisting of R³²-substituted T,R³²-substituted—T—(C₁–C₆)alkyl, R³²-substituted—(C₂–C₄)alkenyl,R³²-substituted—(C₁–C₆)alkyl, R³²-substituted—(C₃–C₇)cycloalkyl andR³²-substituted—(C₃–C₇)cycloalkyl(C₁–C₆)alkyl; R³¹ is independentlyselected from the group consisting of H and (C₁–C₄)alkyl; T isindependently selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R³² isindependently selected from 1–3 substituents which are eachindependently selected from the group consisting of H, halo,(C₁–C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁–C₄)alkoxy, methylenedioxy,oxo, (C₁–C₄)alkylsulfanyl, (C₁–C₄)alkylsulfinyl, (C₁–C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁–C₄)alkyl, —C(O)—N((C₁–C₄)alkyl)₂,—C(O)—(C₁–C₄)alkyl, —C(O)—(C₁–C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁–C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; G¹ isrepresented by the structure:

wherein R³³ is independently selected from the group consisting ofunsubstituted alkyl, R³⁴-substituted alkyl, (R³⁵)(R³⁶)alkyl—,

R³⁴ is one to three substituents, each R³⁴ being independently selectedfrom the group consisting of HOOC—, HS—, (CH₃)S—, H₂N—, (NH₂)(NH)C(NH)—,(NH₂)C(O)— and HOOCCH(NH₃ ⁺)CH₂SS—; R³⁵ is independently selected fromthe group consisting of H and NH₂—; R³⁶ is independently selected fromthe group consisting of H, unsubstituted alkyl, R³⁴-substituted alkyl,unsubstituted cycloalkyl and R³⁴-substituted cycloalkyl; G² isrepresented by the structure:

wherein R³⁷ and R³⁸ are each independently selected from the groupconsisting of (C₁–C₆)alkyl and aryl; R²⁶ is one to five substituents,each R²⁶ being independently selected from the group consisting of: a)H; b) —OH; c) —OCH₃; d) fluorine; e) chlorine; f) —O—G; g) —O—G¹; h)—O—G²; i) —SO₃H; and j) —PO₃H; provided that when R¹ is H, R²⁶ is not H,—OH, —OCH₃ or —O—G; Ar¹ is aryl, R¹⁰-substituted aryl, heteroaryl orR¹⁰-substituted heteroaryl; Ar² is aryl, R¹¹-substituted aryl,heteroaryl or R¹¹-substituted heteroaryl; L is selected from the groupconsisting of: a) a covalent bond; b) —(CH₂)_(q)—, wherein q is 1–6; c)—(CH₂)_(e)—E—(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene, —NR²²— or—S(O)₀₋₂—, e is 0–5 and r is 0–5, provided that the sum of e and r is1–6; d) —(C₂–C₆)alkenylene—; e) —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃–C₆cycloalkylene, f is 1–5 and g is 0–5, provided that the sum of fand g is 1–6; and f)

wherein M is —O—, —S—, —S(O)—or —S(O)₂—; X, Y and Z are eachindependently selected from the group consisting of —CH₂—,—CH(C₁–C₆)alkyl- and —C(di-(C₁–C₆)alkyl)—; R⁸ is selected from the groupconsisting of H and alkyl; R¹⁰ and R¹¹ are each independently selectedfrom the group consisting of 1–3 substituents which are eachindependently selected from the group consisting of (C₁–C₆)alkyl, —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹, —O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰,—NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹, —NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹,—CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰, S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹,—O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁–C₆alkylene)—COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃, —CN,—NO₂ and halo; R¹⁵ and R¹⁷are each independently selected from the groupconsisting of —OR¹⁹, —OC(O)R¹⁹, —OC(O)OR²¹, —OC(O)NR¹⁹R²⁰; R¹⁶ andR¹⁸are each independently selected from the group consisting of H,(C₁–C₆)alkyl and aryl; or R¹⁵ and R¹⁶ together are ═O, or R¹⁷and R¹⁸together are ═O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is0 or 1; m, n and p are each independently selected from 0–4; providedthat at least one of s and t is 1, and the sum of m, n, p, s and t is1–6; provided that when p is 0 and t is 1, the sum of m, n and p is 1–5;and provided that when p is 0 and s is 1, the sum of m, t and n is 1–5;v is 0 or 1; j and k are each independently 1–5, provided that the sumof j, k and v is 1–5; Q is a bond, —(CH₂)_(q)—, wherein q is 1–6, or,with the 3-position ring carbon of the azetidinone, forms the spirogroup

wherein R¹² is

R¹³ and R¹⁴ are each independently selected from the group consisting of—CH₂—, —CH(C₁–C₆ alkyl)—, —C(di-(C₁–C₆) alkyl), —CH═CH— and —C(C₁–C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁–C₆ alkyl)— group; a and bare each independently 0, 1, 2 or 3, provided both are not zero;provided that when R¹³is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, a is 1;provided that when R¹⁴ is —CH═CH— or —C(C₁–C₆ alkyl)═CH—, b is 1;provided that when a is 2 or 3, the R¹³'s can be the same or different;and provided that when b is 2 or 3, the R¹⁴'s can be the same ordifferent; and when Q is a bond and L is

then Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are each independently selected from the group consisting ofH, (C₁–C₆)alkyl, aryl and aryl-substituted (C₁–C₆)alkyl; R²¹ is(C₁–C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁–C₆)alkyl, aryl(C₁–C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are each independentlyselected from the group consisting of 1–3 substituents which are eachindependently selected from the group consisting of H, (C₁–C₆)alkyl,(C₁–C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halo; and R²⁵ is H, —OH or(C₁–C₆)alkoxy.
 11. The composition according to claim 1, wherein the atleast one obesity medication is selected from the group consisting ofnoradrenergic agents, serotonergic agents, thermogenic agents andcombinations thereof.
 12. The composition according to claim 11, whereinthe noradrenergic agent is selected from the group consisting ofdiethylpropion, mazindol, phenylpropanolamine, phentermine,phendimetrazine, phendamine tartrate, methamphetamine, phendimetrazinetartrate and combinations thereof.
 13. The composition according toclaim 11, wherein the serotonergic agent is selected from the groupconsisting of sibutramine, fenfluramine, dexfenfluramine, fluoxetine,fluvoxamine, paroxtine and combinations thereof.
 14. The compositionaccording to claim 11, wherein the thermogenic agent is selected fromthe group consisting of ephedrine, caffeine, theophylline, selectiveβ3-adrenergic agonists and combinations thereof.
 15. The compositionaccording to claim 1, wherein the at least one obesity controlmedication is administered to a mammal in an amount ranging from about 1to about 1000 milligrams of obesity medication per day.
 16. Thecomposition according to claim 1, wherein the at least one sterol or5α-stanol absorption inhibitor is administered to a mammal in an amountranging from about 0.1 to about 1000 milligrams of sterol or 5α-stanolabsorption inhibitor per day.
 17. The composition according to claim 1,wherein the at least one obesity control medication is an alpha-blockingagent.
 18. The composition according to claim 1, wherein the at leastone obesity control medication is a kainite orD,L-a-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) receptorantagonist.
 19. The composition according to claim 1, wherein the atleast one obesity control medication is a leptin-lipolysis stimulatedreceptor.
 20. The composition according to claim 1, wherein the at leastone obesity control medication is a phosphodiesterase enzyme inhibitor.21. The composition according to claim 1, wherein the at least oneobesity control medication is a compound having nucleotide sequences ofthe mahogany gene.
 22. The composition according to claim 1, wherein theat least one obesity control medication is a fibroblast growth factor-10polypeptide.
 23. The composition according to claim 1, wherein the atleast one obesity control medication is a monoamine oxidase inhibitor.24. The composition according to claim 23, wherein the monoamine oxidaseinhibitor is selected from the group consisting of befloxatone,moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone,pirlindol, amiflamine, sercloremine, bazinaprine, lazabemide,milacemide, caroxazone and combinations thereof.
 25. The compositionaccording to claim 1, wherein the at least one obesity controlmedication is a compound for increasing lipid metabolism.
 26. Thecomposition according to claim 1, wherein the at least one obesitycontrol medication is a lipase inhibitor.
 27. A pharmaceuticalcomposition for the treatment or of obesity or lowering a concentrationof a sterol or 5α-stanol in plasma of a mammal, comprising atherapeutically effective amount of the composition of claim 1 and apharmaceutically acceptable carrier.
 28. A method of treating or obesityor lowering a concentration of a sterol or 5α-stanol in plasma of amammal, comprising the step of administering to a mammal in need of suchtreatment an effective amount of the composition of claim
 1. 29. Atherapeutic combination comprising: (a) a first amount of at least oneobesity control medication, and (b) a second amount of at least onesterol absorption inhibitor or 5α-stanol absorption inhibitor; whereinthe first amount and the second amount together comprise atherapeutically effective amount for the treatment or of obesity orlowering a concentration of a sterol or 5α-stanol in plasma of asubject.
 30. The therapeutic combination of claim 29, wherein the atleast one sterol or 5α-stanol absorption inhibitor is represented byFormula (I):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein: Ar¹ and Ar² are independently selected from the groupconsisting of aryl and R⁴-substituted aryl; Ar³is aryl or R⁵-substitutedaryl; X, Y and Z are independently selected from the group consisting of—CH₂—, —CH(lower alkyl)— and —C(dilower alkyl)—; R and R² areindependently selected from the group consisting of —OR⁶, —O(CO)R⁶,—O(CO)OR⁹ and —O(CO)NR⁶R⁷; R¹ and R³ are independently selected from thegroup consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is 0or 1; m, n and p are independently selected from 0, 1, 2, 3 or 4;provided that at least one of q and r is 1, and the sum of m, n, p, qand r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1,the sum of m, q and n is 1, 2, 3, 4 or 5; R⁴ is 1–5 substituentsindependently selected from the group consisting of lower alkyl, —OR⁶,—O(CO)R⁶, O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷,—NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, —(loweralkylene)COOR⁶, —CH═CH—COOR⁶, —CF₃, —CN, —NO₂ and halogen; R⁵ is 1–5substituents independently selected from the group consisting of —OR⁶,—O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷,—NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, —(loweralkylene)COOR⁶ and —CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independentlyselected from the group consisting of hydrogen, lower alkyl, aryl andaryl-substituted lower alkyl; and R⁹ is lower alkyl, aryl oraryl-substituted lower alkyl.
 31. The therapeutic combination accordingto claim 29, wherein the at least one obesity medication is administeredconcomitantly with the at least one sterol or 5α-stanol absorptioninhibitor.
 32. The therapeutic combination according to claim 29,wherein the at least one obesity medication and the at least one sterolor 5α-stanol absorption inhibitor are present in separate treatmentcompositions.
 33. A method of treating or obesity or lowering aconcentration of a sterol in plasma of a subject, comprising the step ofadministering to a subject in need of such treatment an effective amountof the composition of claim
 29. 34. A method of treating or obesitycomprising the step of administering to a subject in need of suchtreatment an effective amount of a composition comprising at least onesterol or 5α-stanol absorption inhibitor.
 35. A method of treating orobesity comprising the step of administering to a subject in need ofsuch treatment an effective amount of a composition comprising at leastone sterol absorption inhibitor represented by Formula (II) below: